Inhibitors of e1 activating enzymes

ABSTRACT

This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.

RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.11/346,469, filed Feb. 2, 2006, which claims the benefit of U.S.Provisional Patent Application No. 60/650,433, filed Feb. 4, 2005, whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compounds, compositions and methods for thetreatment of various disorders, particularly disorders of cellproliferation, including cancers, and inflammatory disorders. Inparticular, the invention provides compounds which inhibit the activityof E1 type activating enzymes.

BACKGROUND OF THE INVENTION

The post-translational modification of proteins by ubiquitin-likemolecules (ubls) is an important regulatory process within cells,playing key roles in controlling many biological processes includingcell division, cell signaling and the immune response. Ubls are smallproteins that are covalently attached to a lysine on a target proteinvia an isopeptide linkage with a C-terminal glycine of the ubl. Theubiquitin-like molecule alters the molecular surface of the targetprotein and can affect such properties as protein-protein interactions,enzymatic activity, stability and cellular localization of the target.

Ubiquitin and other ubls are activated by a specific E1 enzyme whichcatalyzes the formation of an acyl-adenylate intermediate with theC-terminal glycine of the ubl. The activated ubl molecule is thentransferred to the catalytic cysteine residue within the E1 enzymethrough formation of a thioester bond intermediate. The E1-ublintermediate and an E2 associate, resulting in a thioester exchangewherein the ubl is transferred to the active site cysteine of the E2.The ubl is then conjugated to the target protein, either directly or inconjunction with an E3 ligase, through isopeptide bond formation withthe amino group of a lysine side chain in the target protein.

The biological consequence of ubl modification depends on the target inquestion. Ubiquitin is the best characterized of the ubls and aconsequence of modification by ubiquitination is the degradation ofpoly-ubiquitinated proteins by the 26S proteasome. Ubiquitin isconjugated to its target proteins through an enzymatic cascade involvingits specific E1 activating enzyme, Uba1 (ubiquitin activating enzyme,UAE), a conjugating enzyme from the family of E2s, and a ubiquitinligase from either the RING or HECT classes of E3s. See, Huang et al.,Oncogene. 23:1958-71 (2004). Target specificity is controlled by theparticular combination of E2 and E3 protein, with >40 E2s and >100 E3sbeing known at present. In addition to ubiquitin, there are at least 10ubiquitin-like proteins, each believed to be activated by a specific E1activating enzyme and processed through similar but distinct downstreamconjugation pathways. Other ubls for which E1 activating enzymes havebeen identified include Nedd8 (APPBP1-Uba3), ISG15 (UBE1L) and the SUMOfamily (Aos1-Uba2).

The ubl Nedd8 is activated by the heterodimer Nedd8-activating enzyme(APPBP1-Uba3) (NAE) and is transferred to a single E2 (Ubc12),ultimately resulting in ligation to cullin proteins. The function ofneddylation is the activation of cullin-based ubiquitin ligases involvedin the ubiquitination and hence turnover of many cell cycle and cellsignaling proteins, including p27 and I-κB. See Pan et al., Oncogene.23:1985-97, (2004). The ubl SUMO is activated by the heterodimer sumoactivating enzyme (Aos1-Uba2) (SAE) and is transferred to a single E2(Ubc9), followed by coordination with multiple E3 ligases, ultimatelyresulting in sumoylation of target proteins. Sumo modification canaffect the cellular localization of target proteins and proteinsmodified by SUMO family members are involved in nuclear transport,signal transduction and the stress response. See Seeler and Dejean, NatRev Mol Cell Biol. 4:690-9, (2003). The function of sumoylation includesactivation of cell signaling pathways (e.g., cytokine, WNT, growthfactor, and steroid hormone signaling) involved in transcriptionregulation; as well as pathways involved in control of genomic integrity(e.g., DNA replication, response to DNA damage, recombination andrepair). See Muller et al, Oncogene. 23:1998-2006, (2004). There areother ubls (e.g., ISG15, FAT10, Apg12p) for which the biologicalfunctions are still under investigation.

A particular pathway of importance which is regulated via E1 activatingenzyme activities is the ubiquitin-proteasome pathway (UPP). Asdiscussed above, the enzymes UAE and NAE regulate the UPP at twodifferent steps in the ubiquitination cascade. UAE activates ubiquitinin the first step of the cascade, while NAE, via activation of Nedd8, isresponsible for the activation of the cullin based ligases, which inturn are required for the final transfer of ubiquitin to certain targetproteins A functional UPP pathway is required for normal cellmaintenance. The UPP plays a central role in the turnover of many keyregulatory proteins involved in transcription, cell cycle progressionand apoptosis, all of which are important in disease states, includingtumor cells. See, e.g., King et al., Science 274: 1652-1659 (1996);Vorhees et al., Clin. Cancer Res., 9: 6316-6325 (2003); and Adams etal., Nat. Rev. Cancer, 4: 349-360 (2004). Proliferating cells areparticularly sensitive to inhibition of the UPP. See, Drexler, Proc.Natl. Acad. Sci., USA 94: 855-860 (1977). The role of the UPP pathway inoncogenesis has led to the investigation of proteasome inhibition as apotential anticancer therapy. For example, modulation of the UPP pathwayby inhibition of the 26S proteasome by VELCADE® (bortezomib) has provento be an effective treatment in certain cancers and is approved for thetreatment of relapsed and refractory multiple myeloma. Examples ofproteins whose levels are controlled by cullin-based ubiquitin ligaseswhich are downstream of NAE and UAE activity include the CDK inhibitorp27^(Kip1) and the inhibitor of NFκB, IκB. See, Podust et al., Proc.Natl. Acad. Sci., 97: 4579-4584, (2000), and Read et al., Mol. Cell.Biol., 20: 2326-2333, (2000). Inhibition of the degradation of p27 isexpected to block the progression of cells through the G1 and S phasesof the cell cycle. Interfering with the degradation of IκB shouldprevent the nuclear localization of NF-κB, transcription of variousNF-κB-dependent genes associated with the malignant phenotype, andresistance to standard cytotoxic therapies. Additionally, NF-κB plays akey role in the expression of a number of pro-inflammatory mediators,implicating a role for such inhibitors in inflammatory diseases.Furthermore, inhibition of UPP has been implicated as a useful targetfor additional therapeutics, such as inflammatory disorders, including,e.g., rheumatoid arthritis, asthma, multiple sclerosis, psoriasis andreperfusion injury; neurodegenerative disorders, including e.g.,Parkinson's disease, Alzheimer's disease, triplet repeat disorders;neuropathic pain; ischemic disorders, e.g., stroke, infarction, kidneydisorders; and cachexia. See, e.g., Elliott and Ross, Am J Clin Pathol.116:637-46 (2001); Elliott et al., J Mol Med. 81:235-45 (2003); Tarlacand Storey, J. Neurosci. Res. 74: 406-416 (2003); Mori et al.,Neuropath. Appl. Neurobiol., 31: 53-61 (2005); Manning, Curr PainHeadache Rep. 8: 192-8 (2004); Dawson and Dawson, Science 302: 819-822(2003); Kukan, J Physiol Pharmacol. 55: 3-15 (2004); Wojcik andDiNapoli, Stroke. 35:1506-18 (2004); Lazarus et al., Am J Physiol.27:E332-41 (1999).

Targeting E1 activating enzymes provides a unique opportunity tointerfere with a variety of biochemical pathways important formaintaining the integrity of cell division and cell signaling. E1activating enzymes function at the first step of ubl conjugationpathways; thus, inhibition of an E1 activating enzyme will specificallymodulate the downstream biological consequences of the ubl modification.As such, inhibition of these activating enzymes, and the resultantinhibition of downstream effects of ubl-conjugation, represents a methodof interfering with the integrity of cell division, cell signaling, andseveral aspects of cellular physiology which are important for diseasemechanisms. Thus, E1 enzymes such as UAE NAE, and SAE, as regulators ofdiverse cellular functions, are potentially important therapeutictargets for the identification of novel approaches to treatment ofdiseases and disorders.

DESCRIPTION OF THE INVENTION

This invention provides compounds that are effective inhibitors of E1activating enzymes, particularly NAE. The compounds are useful forinhibiting E1 activity in vitro and in vivo, and are useful for thetreatment of disorders of cell proliferation, particularly cancers, andother disorders associated with E1 activity. Compounds of the inventionare of the general formula I-A:

or a pharmaceutically acceptable salt thereof,

wherein:

Ring A is selected from the group consisting of

wherein one ring nitrogen atom in Ring A optionally is oxidized;

-   -   X is —CH₂—, —CHF—, —CF₂—, —NH—, or —O—;    -   Y is —O—, —S—, or —C(R^(m))(R^(n))—;    -   each R^(h) independently is hydrogen, halo, —CN, —OH, —O—(C₁₋₄        aliphatic), —NH₂, —NH—(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,        —SH, —S—(C₁₋₄ aliphatic), or an optionally substituted C₁₋₄        aliphatic group;    -   R^(j) is hydrogen, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally        substituted aliphatic, aryl, or heteroaryl group;    -   R^(k) is hydrogen, halo, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally        substituted C₁₋₄ aliphatic group;    -   R^(m) is hydrogen, fluoro, —N(R⁴)₂, or an optionally substituted        C₁₋₄ aliphatic group, and R^(n) is hydrogen, fluoro, or an        optionally substituted C₁₋₄ aliphatic group, or R^(m) and R^(n)        together form ═O or ═C(R⁵)₂;    -   R¹ is hydrogen, chloro, bromo, fluoro, iodo, —NR⁷R⁸, —R⁹, —SH,        —SCH₃, —S—R¹⁰, —OH, —OCH₃, or —O—R¹¹;    -   R² is hydrogen, chloro, bromo, fluoro, iodo, —N(R⁶)₂, —CN,        —O—(C₁₋₄ aliphatic), —OH, —SR⁶, or an optionally substituted        C₁₋₄ aliphatic group;    -   R^(3a) is selected from the group consisting of hydrogen,        fluoro, —CN, —N₃, hydroxy, —OR²¹, —NH₂, —NH(R²¹), —N(H)CO₂R²¹,        —N(H)C(O)R²¹, —CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹, —OC(O)OR²¹,        —C₁₋₄ fluoroaliphatic, or a —C₁₋₄ aliphatic optionally        substituted with one or two substituents independently selected        from the group consisting of —OR^(5x), —N(R^(4x))(R^(4y)),        —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or R^(3a) and R^(3c)        together form a bond;    -   R^(3b) is selected from the group consisting of hydrogen,        fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R³ is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, hydroxy, —OR²¹, —NH₂, —NH(R²¹), —N(H)CO₂R²¹,        —N(H)C(O)R²¹, —CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹, —OC(O)OR²¹,        —C₁₋₄ fluoroaliphatic, or a —C₁₋₄ aliphatic optionally        substituted with one or two substituents independently selected        from the group consisting of —OR^(5x), —N(R^(4x))(R^(4y)),        —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(c)        together form a bond;    -   R^(3d) is selected from the group consisting of hydrogen,        fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   each R⁴ is independently hydrogen, fluoro, C₁₋₄ aliphatic, or        C₁₋₄ fluoroaliphatic; or two R⁴, taken together with the carbon        atom to which they are attached, form a 3- to 6-membered        carbocyclic ring; or one R⁴, taken together with R⁵ and the        intervening carbon atoms, forms a 3- to 6-membered spirocyclic        ring; or two R⁴ together form ═O;    -   R⁵ is hydrogen, or C₁₋₄ aliphatic; or R⁵, taken together with        one R⁴ and the intervening carbon atoms, forms a 3- to        6-membered spirocyclic ring;    -   R^(5′) is hydrogen, or C₁₋₄ aliphatic;    -   each R⁶ is independently hydrogen or C₁₋₄ aliphatic;    -   R⁷ is an optionally substituted C₁₋₁₀ aliphatic, aryl,        heteroaryl, or heterocyclyl group;    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   R⁹ is —V—Z—R^(12a), —V—Z—R^(12b), —R^(12c), or an optionally        substituted aliphatic, aryl, heterocyclyl, or heteroaryl group;    -   R¹⁰ is an unsubstituted C₂₋₁₀ aliphatic, a substituted C₁₋₁₀        aliphatic, or an optionally substituted aryl, heteroaryl, or        heterocyclyl;    -   R¹¹ is an unsubstituted C₂₋₁₀ aliphatic, a substituted C₁₋₁₀        aliphatic, or an optionally substituted aryl, heteroaryl, or        heterocyclyl;    -   R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted;    -   R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted, or an optionally substituted 5- or 6-membered aryl,        heteroaryl, or heterocyclyl ring; or    -   R^(4x) and R^(4y), taken together with the nitrogen atom to        which they are attached, form an optionally substituted 4- to        8-membered heterocyclyl ring having, in addition to the nitrogen        atom, 0-2 ring heteroatoms independently selected from N, O, and        S;    -   each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀        ar(C₁₋₄)alkyl;    -   V is —S(O)₂—, —S(O)—, —C(O)O—, —C(O)—, —C(NR¹³)═N—,        —C(═N(R¹³))—N(R¹³)—, —C(OR¹¹)═N—, —CON(R¹³)—, —N(R¹³)C(O)—,        —N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂—, —N(R¹³)SO₂—N(R¹³)—,        —N(R¹³)CO₂—, —SO₂N(R¹³)—, —OC(O)—, —OC(O)O—, —OC(O)N(R¹³)—,        —N(R¹³)—N(R¹³)—;    -   Z is an optionally substituted C₁₋₆ alkylene chain, wherein the        alkylene chain is optionally interrupted by —C(R¹³)═C(R¹³)—,        —C≡C—, —O—, —S—, —N(R¹³)—, —N(R¹³)CO—, —N(R¹³)CO₂—,        —C(O)N(R¹³)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,        —N(R¹³)C(O)N(R¹³)—, —N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—,        —S(O)₂—, —N(R¹³)S(O)₂—, —S(O)₂N(R¹³)—;    -   R^(12a) is an optionally substituted aryl, heteroaryl,        heterocyclyl, or cycloaliphatic group;    -   R^(12b) is halo, —NO₂, —CN, —OR¹⁴, —N(R¹⁶)₂, —N(R¹⁶)C(O)R¹⁵,        —N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)CO₂R¹⁴, —O—CO₂—R¹⁴, —OC(O)N(R¹⁶)₂,        —OC(O)R¹⁴, —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)—OR¹⁵, —N(R¹⁶)S(O)₂R¹⁵, or        —N(R¹⁶)SO₂—N(R¹⁶)₂, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴, —S(O)R¹⁵,        —SO₂R¹⁵, —SO₂—N(R¹⁶)₂, —C(R¹⁴)═N—OR¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴,        —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(═NR¹⁶)—N(R¹⁶)₂, or —C(═NR¹⁶)—OR¹⁴;    -   R^(12c) is —NO₂, —CN, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂,        —C(R¹⁴)═N—OR¹⁴, —N(R¹⁶)C(O)R¹⁵, —N(R¹⁶)C(O)N(R¹⁶)₂, —O—CO₂—R¹⁴—,        —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴,        —C(O)N(R¹⁶)₂, —C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴,        —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)—OR¹⁵, —N(R¹⁶)S(O)₂R¹⁵, or        —N(R¹⁶)SO₂—N(R¹⁶)₂;    -   each R¹³ is independently hydrogen, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R¹⁴ independently is hydrogen, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R¹⁵ independently is an optionally substituted aliphatic,        or aryl group;    -   each R¹⁶ independently is an optionally substituted aliphatic,        aryl, heteroaryl, or heterocyclyl group; or two R¹⁶ on the same        nitrogen atom, taken together with the nitrogen atom, form an        optionally substituted five to eight membered heterocyclyl ring        having, in addition to the nitrogen atom, zero to two additional        ring heteroatoms selected from the group consisting of N, O, and        S;    -   each R²¹ independently is an optionally substituted C₁₋₁₀        aliphatic, aryl, heteroaryl, or heterocyclyl group; and    -   m is 1, 2, or 3.

Compounds of the invention include those described generally above, andare further defined and illustrated by the detailed description andexamples herein.

As used herein, the term “E1,” “E1 enzyme,” or “E1 activating enzyme”refers to any one of a family of related ATP-dependent activatingenzymes involved in activating or promoting ubiquitin or ubiquitin-like(collectively “ubl”) conjugation to target molecules. E1 activatingenzymes function through an adenylation/thioester intermediate formationto transfer the appropriate ubl to the respective E2 conjugating enzymethrough a transthiolation reaction. The resulting activated ubl-E2promotes ultimate conjugation of the ubl to a target protein. A varietyof cellular proteins that play a role in cell signaling, cell cycle, andprotein turnover are substrates for ubl conjugation which is regulatedthrough E1 activating enzymes (e.g., NAE, UAE, SAE). Unless otherwiseindicated by context, the term “E1 enzyme” is meant to refer to any E1activating enzyme protein, including, without limitation, nedd8activating enzyme (NAE (APPBP1/Uba3)), ubiquitin activating enzyme (UAE(Uba1)), sumo activating enzyme (SAE (Aos1/Uba2)), or ISG15 activatingenzyme (Ube1L), preferably human NAE, SAE or UAE, and more preferablyNAE.

The term “E1 enzyme inhibitor” or “inhibitor of E1 enzyme” is used tosignify a compound having a structure as defined herein, which iscapable of interacting with an E1 enzyme and inhibiting its enzymaticactivity. Inhibiting E1 enzymatic activity means reducing the ability ofan E1 enzyme to activate ubiquitin like (ubl) conjugation to a substratepeptide or protein (e.g., ubiquitination, neddylation, sumoylation). Invarious embodiments, such reduction of E1 enzyme activity is at leastabout 50%, at least about 75%, at least about 90%, at least about 95%,or at least about 99%. In various embodiments, the concentration of E1enzyme inhibitor required to reduce an E1 enzymatic activity is lessthan about 1 μM, less than about 500 nM, less than about 100 nM, lessthan about 50 nM, or less than about 10 nM.

In some embodiments, such inhibition is selective, i.e., the E1 enzymeinhibitor reduces the ability of one or more E1 enzymes (e.g., NAE, UAE,or SAE) to promote ubl conjugation to substrate peptide or protein at aconcentration that is lower than the concentration of the inhibitor thatis required to produce another, unrelated biological effect. In somesuch embodiments, the E1 enzyme inhibitor reduces the activity of one E1enzyme at a concentration that is lower than the concentration of theinhibitor that is required to reduce enzymatic activity of a differentE1 enzyme. In other embodiments, the E1 enzyme inhibitor also reducesthe enzymatic activity of another E1 enzyme, preferably one that isimplicated in regulation of pathways involved in cancer (e.g., NAE andUAE).

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

The term “aliphatic”, as used herein, means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation, but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof, such as cycloalkyl, (cylcoalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl. In various embodiments, thealiphatic group has one to ten, one to eight, one to six, one to four,or one, two, or three carbons.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight and branched chain aliphatic grouphaving from one to twelve carbon atoms. For purposes of the presentinvention, the term “alkyl” will be used when the carbon atom attachingthe aliphatic group to the rest of the molecule is a saturated carbonatom. However, an alkyl group may include unsaturation at other carbonatoms. Thus, alkyl groups include, without limitation, methyl, ethyl,propyl, allyl, propargyl, butyl, pentyl, and hexyl. The term “alkoxy”refers to an —O-alkyl radical.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on a cycloaliphatic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings. Nonlimiting examples include indanyl,5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on an arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aromatic ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthaiazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 it electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Thus, when used in reference to a ring atom of a heteroaryl,the term “nitrogen” includes an oxidized nitrogen (as in pyridineN-oxide). Certain nitrogen atoms of 5-membered heteroaryl groups alsoare substitutable, as further defined below. Heteroaryl groups include,without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.

In some embodiments, two adjacent substituents on a heteroaryl ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring”, or “heteroaryl group”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “aromatic ring” and “aromatic ring system”refer to an optionally substituted mono-, bi-, or tricyclic group having0-6, preferably 0-4 ring heteroatoms, and having 6, 10, or 14 πelectrons shared in a cyclic array. Thus, the terms “aromatic ring” and“aromatic ring system” encompass both aryl and heteroaryl groups.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylallyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers typically comprise an atomsuch as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—, —C(O)NH—,or a chain of atoms, such as an alkylene chain. The molecular mass of alinker is typically in the range of about 14 to 200, preferably in therange of 14 to 96 with a length of up to about six atoms. In someembodiments, the linker is a C₁₋₆ alkylene chain which is optionallysubstituted.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from one to six, from one to four, from oneto three, from one to two, or from two to three. A substituted alkylenechain is a polymethylene group in which one or more methylene hydrogenatoms is replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group. An alkylenechain also may be substituted at one or more positions with an aliphaticgroup or a substituted aliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group. Examplesof suitable “interrupting functional groups” include —C(R*)═C(R*)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—, —N(R*)—, —N(R⁺)CO—,—N(R⁺)C(O)N(R⁺)—, —N(R⁺)CO₂—, —C(O)N(R⁺)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —OC(O)N(R⁺)—, —C(NR⁺)═N, —C(OR*)═N—, —N(R⁺)—N(R⁺)—,or —N(R⁺)S(O)₂—. Each R⁺, independently, is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or twoR⁺ on the same nitrogen atom, taken together with the nitrogen atom,form a five to eight membered aromatic or non-aromatic ring having, inaddition to the nitrogen atom, zero to two ring heteroatoms selectedfrom N, O, and S. Each R* independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with —O—include —CH₂OCH₂—, —CH₂O(CH₂)₂—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—,—(CH₂)₂OCH₂—, —(CH₂)₂O(CH₂)₂—, —(CH₂)₂O(CH₂)₃—, —(CH₂)₃O(CH₂)—,—(CH₂)₃O(CH₂)₂—, and —(CH₂)₄O(CH₂)—. Other examples of alkylene chainsthat are “interrupted” with functional groups include —CH₂GCH₂—,—CH₂G(CH₂)₂—, —CH₂G(CH₂)₃—, —CH₂G(CH₂)₄—, —(CH₂)₂GCH₂—, —(CH₂)₂G(CH₂)₂—,—(CH₂)₂G(CH₂)₃—, —(CH₂)₃G(CH₂)—, —(CH₂)₃G(CH₂)₂—, and —(CH₂)₄G(CH₂)—,wherein G is one of the “interrupting” functional groups listed above.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above and thevariables V and Z, are intended to be read from left to right, with acorresponding left-to-right reading of the formula or structure in whichthe variable appears.

One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations are not sufficiently stable for pharmaceutical use. Onlystable or chemically feasible compounds are within the scope of thepresent invention. A stable or chemically feasible compound is one inwhich the chemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., preferably from about−20° C. to about +40° C., in the absence of moisture or other chemicallyreactive conditions, for at least a week, or a compound which maintainsits integrity long enough to be useful for therapeutic or prophylacticadministration to a patient.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The term “substitutable”, when used inreference to a designated atom, means that attached to the atom is ahydrogen radical, which can be replaced with the radical of a suitablesubstituent.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met. Unless otherwise indicated, an optionally substituted group mayhave a substituent at each substitutable position of the group, and thesubstituents may be either the same or different. As used herein, theterm “independently selected” means that the same or different valuesmay be selected for multiple instances of a given variable in a singlecompound.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂, —NR⁺CO₂R^(o), —O—CO₂R*,—OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*, —C(O)R*, —C(O)N(R⁺)₂,—C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*, —N(R⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂,—NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —P(O)(R*)₂, —P(O)(OR*)₂, —O—P(O)—OR*, and—P(O)(NR⁺)—N(R⁺)₂, wherein R^(o) is an optionally substituted aliphaticor aryl group, and R⁺ and R* are as defined above, or two adjacentsubstituents, taken together with their intervening atoms, form a 5- to6-membered unsaturated or partially unsaturated ring having 0-3 ringatoms selected from the group consisting of N, O, and S.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing: ═O, ═S, ═C(R*)₂, ═N—N(R⁺)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(o), ═N—NHSO₂R^(o), or ═N—R*, where each R* and R^(o) is asdefined above. For the purposes of clarity, the term “substitutedaliphatic” refers to an aliphatic group having at least onenon-aliphatic substituent.

Suitable substituents on a substitutable nitrogen atom of a heteroarylor heterocyclic ring include —R*, —N(R*)₂, —C(O)R*, —CO₂R*,—C(O)—C(O)R*, —C(O)CH₂C(O)R*, —SO₂R*, —SO₂N(R*)₂, —C(═S)N(R*)₂,—C(═NH)—N(R*)₂, and —NR*SO₂R*; wherein each R* is as defined above.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention. Unlessotherwise stated, structures depicted herein are also meant to includeall stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.By way of example, the compounds of formula I wherein R^(3a) is hydroxycan have R or S configuration at the carbon atom bearing R^(3a). Boththe R and the S stereochemical isomers, as well as all mixtures thereof,are included within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructure except for the replacement of a hydrogen atom by a deuteriumor tritium, or the replacement of a carbon atom by a ¹³C- or¹⁴C-enriched carbon are within the scope of the invention.

Compounds of formula (I-A)are useful in decreasing E1 enzyme activityand treating or ameliorating disorders. Certain of these compounds, asprovided in further detail below, are new. Accordingly, one aspect ofthis invention relates to such compounds, as represented by formula(I-A), as described above, provided that: if Ring A is A-i, X is —O—, Yis —O— or —CH₂—, R² is hydrogen or chloro, R^(3a) is hydroxyl or—OCOR²¹, R^(3b) is hydrogen, R^(3c) is hydroxyl or —OCOR²¹, R^(3d) ishydrogen, R⁴ and R⁵ are each hydrogen, and m is 1; then R¹ is bromo,fluoro, —NR⁷R⁸, —R⁹, —SR¹⁰, or —OR¹¹, R⁷ is a substituted aliphatic, oran optionally substituted aryl, heteroaryl, aralkyl, heteroaralkyl,cycloaliphatic, heterocyclyl, (cycloaliphatic)alkyl, or(heterocyclyl)alkyl, and R⁹ is other than unsubstituted imidazole.

In the compounds of formula (I-A), X is —CH₂—, —CHF—, —CF₂—, —NH—, or—O—. In some embodiments, X is —CH₂—, —NH—, or —O—. In certainembodiments, X is —O—.

In the compounds of formula (I-A), Y is —O—, —S—, or —C(R^(m))(R^(n))—,where R^(m) and R^(n) are as described above. In some embodiments, R^(m)is hydrogen, fluoro, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, orC₁₋₄ aliphatic. In some embodiments, Y is —O— or —CH₂.

In the compounds of formula (I-A), R^(3a) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, hydroxy, —OR²¹, —NH₂,—NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹, —C(O)R²¹, —CON(H)R²¹,—OC(O)N(H)R²¹, —OC(O)R²¹, —OC(O)OR²¹, —C₁₋₄ fluoroaliphatic, or a —C₁₋₄aliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)). In someembodiments R^(3a) is selected from the group consisting of hydrogen,hydroxy, —NH₂, C₁₋₄ aliphatic, fluoro, —CN, C₁₋₄ fluoroaliphatic, —OR²¹,—NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹, —C(O)NHR²¹, —C(O)R²¹, —OC(O)NHR²¹,—OC(O)R²¹, and —OC(O)OR²¹. In some embodiments, R^(3a) is selected fromthe group consisting of hydrogen, —OH, —OCH₃, C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, and fluoro. In certain embodiments, R^(3a) is selectedfrom the group consisting of hydrogen, —OH, —OCH₃, —CH₃, and fluoro. Incertain particular embodiments, R^(3a) is —OH.

In the compounds of formula (I-A), R^(3c) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, hydroxy, —OR²¹, —NH₂,—NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹, —CON(H)R²¹, —OC(O)N(H)R²¹,—OC(O)R²¹, —OC(O)OR²¹, —C₁₋₄ fluoroaliphatic, or a —C₁₋₄ aliphaticoptionally substituted with one or two substituents independentlyselected from the group consisting of —OR^(5x), —N(R^(4x))(R^(4y)),—CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)). In some embodiments, R^(3c) isselected from the group consisting of hydrogen, hydroxy, —NH₂, —C₁₋₄aliphatic, fluoro, —CN, —C₁₋₄ fluoroaliphatic, —OR²¹, —NH(R²¹),—N(H)CO₂R²¹, —N(H)C(O)R²¹, —CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹, and—OC(O)OR²¹. In certain embodiments, R^(3c) is hydrogen, —OH, —OCH₃, orfluoro. In certain particular embodiments, R^(3c) is hydrogen or —OH.

In the compounds of formula (I-A), R^(3b) and R^(3d) are eachindependently selected from the group consisting of hydrogen, fluoro,C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic. In some embodiments, one ofR^(3b) and R^(3d) is C₁₋₄ aliphatic and the other is hydrogen. In someembodiments, R^(3b) and R^(3d) are each hydrogen.

In one embodiment, R^(3a) and R^(3c) are each —OH, and R^(3b) and R^(3d)are each hydrogen. In another embodiment, R^(3a) is —OH, and each ofR^(3b), R^(3c), and R^(3d) is hydrogen. In another embodiment, R^(3a) is—OH, R^(3c) is fluoro or —OCH₃, and R^(3b) and R^(3d) are each hydrogen.In another embodiment, R^(3a) is —OH, R^(3b) is —CH₃, R^(3c) is hydrogenor —OH, and R^(3d) is hydrogen. In another embodiment, R^(3a) and R^(3c)together form a bond, and R^(3b) and R^(3d) are each hydrogen.

In the compounds of formula (I-A), each R⁴ is independently hydrogen,fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic; or two R⁴, takentogether with the carbon atom to which they are attached, form a 3- to6-membered carbocyclic ring; or one R⁴, taken together with R⁵ and theintervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; ortwo R⁴ together form ═O. In some embodiments, each R⁴ independently ishydrogen or C₁₋₄ aliphatic. In some such embodiments, each R⁴independently is hydrogen or —CH₃. In certain embodiments, one R⁴ ishydrogen or —CH₃, and the other R⁴ is hydrogen. In certain particularembodiments, each R⁴ is hydrogen.

In the compounds of formula (I-A), R⁵ is hydrogen or C₁₋₄ aliphatic; orR⁵, taken together with one R⁴ and the intervening carbon atoms, forms a3- to 6-membered spirocyclic ring. In some embodiments, R⁵ is hydrogenor C₁₋₄ aliphatic. In some such embodiments, R⁵ is hydrogen or —CH₃. Incertain embodiments, R⁵ is hydrogen.

In the compounds of formula (I-A), R^(5′) is hydrogen or C₁₋₄ aliphatic.In some embodiments, R^(5′) is hydrogen or C₁₋₄ aliphatic. In some suchembodiments, R^(5′) is hydrogen or —CH₃. In certain embodiments, R^(5′)is hydrogen.

In the compounds of formula (I-A), Ring A is selected from the groupconsisting of:

where R¹, R², R^(h), R^(j) and R^(k) are as defined above and as furtherdefined below.

In the compounds of formula (I-A), R² is hydrogen, chloro, bromo,fluoro, iodo, —N(R⁶)₂, —CN, —O—(C₁₋₄ aliphatic), —OH, —SR⁶, or anoptionally substituted C₁₋₄ aliphatic group. In some embodiments, R² ishydrogen, chloro, or —N(R⁶)₂. In certain embodiments, R² is hydrogen orchloro. In certain particular embodiments, R² is hydrogen.

In some embodiments, the compound of formula (I-A) is characterized byat least one of the following features:

(a) X is —O—;

(b) Y is —O— or —CH₂—;

(c) R^(3a) is —OH;

(d) R^(3b) and R^(3d) are each independently hydrogen or C₁₋₄ aliphatic;

(e) R^(3c) is hydrogen, fluoro, or —OR⁵;

(f) R⁵ and R^(5′) are each hydrogen;

(g) each R⁴ is hydrogen;

(h) each R² is hydrogen;

(i) R^(h) is hydrogen;

(j) R^(j) is hydrogen; and

(k) R^(k) is hydrogen, halo, or C₁₋₄ aliphatic.

One embodiment of the invention relates to a subgenus of the compoundsof formula (I-A) represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein Q is ═N— or ═CH—,and the variables X, Y, R¹, R², R^(3a), R^(3b), R^(1c), R^(3d), R⁴, andR⁵ have the values and preferred values described above for formula(I-A).

The invention also relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein:

-   -   X is —CH₂—, —NH—, or —O—;    -   Y is —O—, or —CH₂—;    -   Q is ═N— or ═CH—;    -   R¹ is chloro, bromo, fluoro, iodo, —NR⁷R⁸, —S—R¹⁰, or —O—R¹¹;    -   R² is hydrogen, chloro, bromo, fluoro, iodo, —N(R⁶)₂, —CN,        —O—(C₁₋₄ aliphatic), —OH, —SR⁶, or an optionally substituted        C₁₋₄ aliphatic group;    -   R^(3a) is selected from the group consisting of hydrogen,        hydroxy, —NH₂, —C₁₋₄ aliphatic, fluoro, —CN, —C₁₋₄        fluoroaliphatic, —OR²¹, —NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹,        —CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹, and —OC(O)OR²¹;    -   R^(3b) is selected from the group consisting of hydrogen,        fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R^(3c) is selected from the group consisting of hydrogen,        hydroxy, —NH₂, —C₁₋₄ aliphatic, fluoro, —CN, —C₁₋₄        fluoroaliphatic, —OR²¹, —NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹,        —CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹, and —OC(O)OR²¹;    -   R^(3d) is selected from the group consisting of hydrogen,        fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   each R⁴ is independently hydrogen or C₁₋₄ aliphatic; or two R⁴,        taken together with the carbon atom to which they are attached,        form a 3- to 6-membered carbocyclic ring; or one R⁴, taken        together with R⁵ and the intervening carbon atoms, forms a 3- to        6-membered spirocyclic ring;    -   R⁵ is hydrogen, or C₁₋₄ aliphatic; or R⁵, taken together with        one R⁴ and the intervening carbon atoms, forms a 3- to        6-membered spirocyclic ring;    -   each R⁶ is independently hydrogen or C₁₋₄ aliphatic;    -   R⁷ is an optionally substituted C₁₋₁₀ aliphatic, aryl,        heteroaryl, or heterocyclyl group;    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   R⁹ is —V—Z—R^(12a), —V—Z—R^(12b), —R^(12c), or an option allyl        substituted aliphatic, aryl, heterocyclyl, or heteroaryl group,        wherein the heteroaryl group is attached at a carbon atom;    -   R¹⁰ is an optionally substituted C₂₋₁₀ aliphatic, aryl,        heteroaryl, or heterocyclyl;    -   R¹¹ is an optionally substituted C₂₋₁₀ aliphatic, aryl,        heteroaryl, or heterocyclyl;    -   V is —S(O)₂—, —S(O)—, —C(O)O—, —C(O)—, —C(NR¹³)═N—,        —C(═N(R¹³))—N(R¹³)—, —C(OR¹¹)═N—, —CON(R¹³)—, —N(R¹³)C(O)—,        —N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂—, —N(R¹³)SO₂—N(R¹³)—,        —N(R¹³)CO₂—, —SO₂N(R¹³)—, —OC(O)—, —OC(O)O—, —OC(O)N(R¹³)—,        —N(R¹³)—N(R¹³)—;    -   Z is an optionally substituted C₁₋₆ alkylene chain, wherein the        alkylene chain is optionally interrupted by —C(R¹³)═C(R¹³)—,        —C≡C—, —O—, —S—, —N(R¹³)—, —N(R¹³)CO—, —N(R¹³)CO₂—,        —C(O)N(R¹³)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,        —N(R¹³)C(O)N(R¹³)—, —N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—,        —S(O)₂—, —N(R¹³)S(O)₂—, —S(O)₂N(R¹³)—;    -   R^(12a) is an optionally substituted aryl, heteroaryl,        heterocyclyl, or cycloaliphatic group;    -   R^(12b) is halo, —NO₂, —CN, —OR¹⁴, —SR¹⁵, —N(R¹⁶)₂,        —N(R¹⁶)C(O)R¹⁵, —N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)CO₂R¹⁴, —O—CO₂—R¹⁴,        —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴, —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵, or        —N(R¹⁶)SO₂—N(R¹⁶)₂, —C(R¹⁴)═C(R¹⁴)₂, —S(O)R¹⁵, —SO₂R¹⁵,        —SO₂—N(R¹⁶)₂, —C(R¹⁴)═N—OR¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴,        —C(O)N(R¹⁶)₂, —C(═NR¹⁶)—N(R¹⁶)₂, or —C(═NR¹⁶)—OR¹⁴;    -   R^(12c) is —NO₂, —CN, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂,        —C(R¹⁴)═N—OR¹⁴, —N(R¹⁶)C(O)R¹⁵, —N(R¹⁶)C(O)N(R¹⁶)₂, —O—CO₂—R¹⁴—,        —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴,        —C(O)N(R¹⁶)₂, —C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴,        —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵, or —N(R¹⁶)SO₂—N(R¹⁶)₂;    -   each R¹³ is independently hydrogen, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R¹⁴ independently is hydrogen, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R¹⁵ independently is an optionally substituted aliphatic,        or aryl group;    -   each R¹⁶ independently is an optionally substituted aliphatic,        aryl, heteroaryl, or heterocyclyl group; or two R¹⁶ on the same        nitrogen atom, taken together with the nitrogen atom, form an        optionally substituted five to eight membered heterocyclyl ring        having, in addition to the nitrogen atom, zero to two additional        ring heteroatoms selected from the group consisting of N, O, and        S; and    -   each R²¹ independently is an optionally substituted C₁₋₁₀        aliphatic, aryl, heteroaryl, or heterocyclyl group.

Various particular embodiments of the invention relate to subgenera ofthe compounds of formula (I-A), represented by formulae (II-A), (II-B),(III-A), (III-B), (IV-A), and (IV-B):

or a pharmaceutically acceptable salt thereof, wherein the variables Q,R¹, R², R^(3a), and R^(3c) have the values and preferred valuesdescribed herein for formulae (I) and (I-A).

Another embodiment of the invention relates to a compound of formula (I)or (I-A), wherein R¹ is an optionally substituted aryl, heteroaryl, orheterocyclyl group. In some such embodiments, the compound ischaracterized by formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is an optionally substituted 5- or 6-membered aryl or heteroarylring having zero to three ring nitrogen atoms and optionally oneadditional ring heteroatom selected from oxygen and sulfur. In someembodiments, two adjacent substituents on Ring B, taken together withthe intervening ring atoms, form an optionally substituted fused 5- or6-membered aromatic or non-aromatic ring having zero to three ringheteroatoms selected from the group consisting of O, N, and S; and

the variables Q, X, Y, R^(j), R², R^(3a), R^(3b), R^(3c), R^(3d), R⁴,R⁵, and m have the values and preferred values described above forformulae (I) and (I-A).

In some embodiments, Ring B is an optionally substituted furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, wherein onering nitrogen atom in Ring B optionally is oxidized. In certainparticular embodiments, Ring B is an optionally substituted phenyl,imidazolyl, or triazolyl.

Substitutable ring carbon atoms in Ring B preferably are substitutedwith zero to two substituents independently selected from the groupconsisting of C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(a17),—R^(b17), —Z¹⁷—R^(a17), and —Z¹⁷—R^(b17), or two adjacent substituentson Ring B, taken together with the intervening ring atoms, form anoptionally substituted fused 5- or 6-membered aromatic or non-aromaticring having 0-3 ring heteroatoms selected from the group consisting ofO, N, and S. The variables Z¹⁷, R^(a17), and R^(b17) have the valuesdescribed below.

Z¹⁷ is an optionally substituted C₁₋₆ alkylene chain, wherein thealkylene chain optionally is interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—,—S—, —S(O)—, —S(O)₂—, —SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—,—NR¹⁵C(O)N(R¹⁵)—, —N(R¹⁵)CO₂—, —N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, or —OC(O)N(R¹⁵)—, and wherein Z¹⁷ or a portionthereof optionally forms part of a 3-7 membered ring. In someembodiments, Z¹⁷ is a C₁₋₆, C₁₋₄, or C₂₋₄ alkylene chain optionallysubstituted with one or two R^(x) or R^(y), wherein R^(x) and R^(y) havethe values and preferred values described above.

Each R^(a17) independently is an optionally substituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic ring.

Each R^(b17) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR^(16c)(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂. In someembodiments, each R^(b17) independently is —CN, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴—C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —C(O)N(R⁴)₂, —CO₂R⁵, or —OR⁵.

In some embodiments, the substitutable ring carbon atoms in Ring B aresubstituted with zero, one, or two substituents independently selectedfrom the group consisting of halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃alkyl), —C₁₋₃ aliphatic, —C₁₋₃ fluoroaliphatic, —O(C₁₋₃fluoroaliphatic), optionally substituted aryl, and optionallysubstituted heteroaryl. Preferred halo groups in R¹⁷ substitutionsinclude F and Cl.

Another embodiment of the invention relates to a compound of formula (I)or (I-A), wherein R¹ is C₁₋₁₀ aliphatic, —Z—R^(12a), —ZR^(12b),-L-Z—R^(11a), -L-Z—R^(12b), -L-R^(12a) or -L-R^(12d); where L is—C(R¹³)═C(R¹³)— or —C≡C—; R^(12d) is —NO₂, —CN, —S(O)R¹⁵, —SO₂R¹³,—SO₂—N(R¹⁶)₂, —CO₂R¹⁴, —C(O)R¹⁴, or —C(O)N(R¹⁶)₂; and the variables Z,R^(12a), R^(12b) and R¹³ are as defined above for formula (I-A). In somesuch embodiments, R¹ is -L-Z—R¹, -L-Z—R^(12b), -L-R^(12a) or -L-R^(12d),where L is —C≡C—.

Another embodiment of the invention relates to a compound of formula (I)or (I-A), wherein R¹ is —V—Z—R^(12a), —V—Z—R^(12b), or —R^(1c). Theinvention also relates to a compound of formula (I) or (I-A), wherein R¹is —Z—V—R^(12a), —V—Z—R^(12b), or —V—R^(12a). The variables V, Z,R^(12a), R^(12b), and R^(12c) are as defined above for formulae (I) and(I-A).

Preferably, V is selected from the group consisting of —S(O)₂—, —C(O)O—,—C(O)—, —CON(R¹³)—, —N(R¹³)C(O)—, —N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂—,—N(R¹³)SO₂—N(R¹³)—, —N(R¹³)CO₂—, and —SO₂N(R¹³)—. More preferably, V isselected from the group consisting of —CON(R¹³)—, —N(R¹³)C(O)—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂—, —N(R¹³)SO₂—N(R¹³)—, and —N(R¹³)CO₂.In certain particular embodiments, V is —N(R¹³)C(O)— or—N(R¹³)C(O)N(R¹³)—.

Preferably, Z is a C₁₋₆ alkylene chain optionally substituted with oneto four substituents. Suitable substituents for Z include thosedescribed generally above for substituted aliphatic groups. In preferredembodiments, Z is optionally substituted with one or two R^(x) or R^(y),where each R^(x) independently is selected from the group consisting of-halo, —OH, —O(C₁₋₄ alkyl), —O(C₁₋₄haloalkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₄alkyl), —CO₂H, —CO₂(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄alkyl),or optionally substituted aryl; and each R^(y) independently is a C₁₋₃aliphatic optionally substituted with R^(x) or an optionally substitutedaryl or heteroaryl group; or two R^(y) on the same carbon atom, takentogether with the carbon atom to which they are attached form a 3- to6-membered cycloaliphatic ring. More preferably, Z is a C₁₋₄ alkylenechain, optionally substituted with C₁₋₃ aliphatic, C₁₋₃ fluoroaliphatic,—F, —OH, —O(C₁₋₃alkyl), —CO₂H, —CO₂(C₁₋₃alkyl), —C(O)NH₂,—C(O)NH(C₁₋₄alkyl), —CN, —N(R)₂, or —C(O)(C₁₋₃alkyl).

Preferably, R^(12c) is selected from the group consisting of —CON(R¹⁶)₂,—N(R¹⁶)C(O)R¹⁵, —N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵, —N(R¹⁶)SO₂—N(R¹⁶)₂,and —N(R¹⁶)CO₂R¹⁵. In certain particular embodiments, R^(12c) is—N(R¹⁶)C(O)R¹⁵, —N(R¹⁶)C(O)N(R¹⁶)₂,

Another embodiment of the invention relates to a compound of formula(VI):

or a pharmaceutically acceptable salt thereof, wherein:

W¹ is —Z—, -L-, —V—, —V—Z—, or —Z—V—;

Ring C is an optionally substituted 5- or 6-membered aryl,cycloaliphatic, heteroaryl, or heterocyclyl ring having zero to threering nitrogen atoms and optionally one additional ring heteroatomselected from oxygen and sulfur; and

the variables Q, X, Y, L, V, Z, R^(j), R², R^(3a), R^(3b), R^(3c),R^(3d), R⁴, R⁵, and m have the values and preferred values describedabove for formulae (I), (I-A), and (V).

In some embodiments, W¹ is —Z— or -L-.

In some embodiments, two adjacent substituents on Ring C, taken togetherwith the intervening ring atoms, form an optionally substituted fused 5-or 6-membered aromatic or non-aromatic ring having zero to three ringheteroatoms selected from the group consisting of O, N, and S.

In some embodiments, Ring C is an optionally substituted mono- orbicyclic aryl, heteroaryl, heterocyclyl or cycloaliphatic group.Exemplary Ring C mono- or bicyclic aryl, heteroaryl, heterocyclyl orcycloaliphatic rings include optionally substituted furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl,pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydro-quinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, benzodioxolyl cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl groups. Incertain particular embodiments, Ring C is an optionally substitutedphenyl ring or an optionally substituted C₃₋₆ cycloaliphatic ring.

Suitable substituents on Ring C include those generally described abovefor substituted aryl, heteroaryl, heterocyclyl and cycloaliphaticgroups. Substitutable ring carbon atoms in Ring C preferably aresubstituted with zero to four, preferably zero to two substituentsindependently selected from the group consisting of C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(a12), —R^(b12), —Z¹²—R^(a12), and—Z¹²—R^(b12). The variables Z¹², R^(a12), and R^(b12) have the valuesdescribed below.

Z¹² is an optionally substituted C₁₋₆ alkylene chain, wherein thealkylene chain optionally is interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—,—S—, —S(O)—, —S(O)₂—, —SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—,—NR¹⁵C(O)N(R¹⁵)—, —N(R¹⁵)CO₂—, —N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, or —OC(O)N(R¹⁵)—, and wherein Z¹² or a portionthereof optionally forms part of a 3-7 membered ring. In someembodiments, Z¹² is a C₁₋₆ or C₁₋₄ alkylene chain optionally substitutedwith one or two R^(x) or R^(y), wherein R^(x) and R^(y) have the valuesand preferred values described above.

Each R^(a12) independently is an optionally substituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic ring.

Each R^(b12) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR₁₆C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂. In someembodiments, each R^(b12) independently is —CN, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴—C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —C(O)N(R⁴)₂, —CO₂R⁵, or —OR⁵.

In some embodiments, the substitutable ring carbon atoms in Ring C aresubstituted with zero, one, or two substituents independently selectedfrom the group consisting of halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃alkyl), —C₁₋₃ aliphatic, —C₁₋₃ fluoroaliphatic, —O(C₁₋₃fluoroaliphatic), optionally substituted aryl, and optionallysubstituted heteroaryl. Preferred halo substituents on Ring C include Fand Cl.

In another embodiment, the invention relates to a compound of formula(I) or (I-A), wherein R¹ is —NR⁷R⁸, and R⁷ is an optionally substitutedaryl, heteroaryl, heterocyclyl or cycloaliphatic group. In moreparticular embodiments, R⁷ is an optionally substituted 5- to 6-memberedmonocyclic or 8- to 10-membered bicyclic aryl or heteroaryl ring, or a3- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclylor cycloaliphatic ring. R⁸ is hydrogen or C₁₋₄ aliphatic, and preferablyis hydrogen.

One embodiment of the invention relates to a compound of formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

R⁸ is hydrogen or C₁₋₄ aliphatic;

Ring D is an optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring; and

the variables X, Y, R^(j), R², R^(3a), R^(3b), R^(3c), R^(3d), R⁴, R⁵,and m have the values and preferred values described above for formulae(I) and (I-A).

In some embodiments, Ring D is a mono- or bicyclic aryl, heteroaryl,heterocyclyl or cycloaliphatic ring. In some such embodiments, Ring Dselected from the group consisting of furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl,indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl,benzothienyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, phenanthridinyl,tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, chromanyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, bicycloheptanyl and bicyclooctanyl.

Suitable substituents on Ring D include those generally described abovefor substituted aryl, heteroaryl, heterocyclyl and cycloaliphaticgroups. Each substitutable saturated ring carbon atom preferably isunsubstituted or substituted with ═O, ═S, ═C(R¹⁴)₂, ═N—N(R¹⁶)₂, ═N—OR¹⁴,═N—NHC(O)R¹⁴, ═N—NHCO₂R¹⁵, ═N—NHSO₂R¹⁵, ═N—R¹⁴, or —R^(d). Eachsubstitutable unsaturated ring carbon atom preferably is unsubstitutedor substituted with —R^(d). Ring D may be unsubstituted or may besubstituted on any one or more of its component rings, wherein thesubstituents may be the same or different.

Each R^(d) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴, —OR¹⁴,—SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂, or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup.

In some embodiments, each R^(d) independently is selected from the groupconsisting of C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(a7),—R^(b7), —Z⁷—R^(a7), and —-Z⁷—R^(b7). The variables Z⁷, R^(a7), andR^(b7) have the values described below.

Z⁷ is an optionally substituted C₁₋₆ alkylene chain, wherein thealkylene chain optionally is interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—,—S—, —S(O)—, —S(O)₂—, —SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—,—NR¹⁵C(O)N(R¹⁵)—, —N(R¹⁵)CO₂—, —N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, or —OC(O)N(R¹⁵)—, and wherein Z⁷ or a portion thereofoptionally forms part of a 3-7 membered ring. In some embodiments, Z⁷ isa C₁₋₆ or C₁₋₄ alkylene chain optionally substituted with one or twoR^(x) or R^(y), wherein R^(x) and R^(y) have the values and preferredvalues described above.

Each R^(a7) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring.

Each R^(b7) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂. In someembodiments, each R^(b7) independently is —CN, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴—C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —C(O)N(R⁴)₂, —CO₂R⁵, or —OR⁵.

In some embodiments, the substitutable ring carbon atoms in Ring D aresubstituted with zero, one, or two substituents independently selectedfrom the group consisting of halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃alkyl), —C₁₋₃ aliphatic, —C₁₋₃ fluoroaliphatic, —O(C₁₋₃fluoroaliphatic), and optionally substituted aryl. Preferred halo groupsubstituents on Ring D include F and Cl.

In certain embodiments, Ring D is an optionally substituted phenyl,naphthyl, or indanyl ring. In certain other embodiments, Ring D is anoptionally substituted 5- or 6-membered heterocyclyl or cycloaliphaticring. Optionally, two adjacent substituents on the heterocyclyl orcycloaliphatic ring, taken together with the intervening carbon atoms,form an optionally substituted fused phenyl ring.

In certain particular embodiments, Ring D is selected from the groupconsisting of:

where

each R^(8p) independently is selected from the group consisting of ═O,fluoro, —OR^(5x), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionallysubstituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), provided that R^(8p) is other than —OR^(5x) whenlocated at a position adjacent to a ring oxygen atom;

s is 0, 1, or 2;

t is 0, 1, or 2; and

the variables R^(4x), R^(4y), and R^(5x) have the values described abovefor formulae (I) and (I-A).

Another embodiment of the invention relates to a compound of formula (I)or (I-A), wherein R¹ is —O—R¹¹, —S—R¹⁰, or —NR⁷R⁸, and R⁷ is anoptionally substituted C₁₋₁₀ aliphatic. Preferably, R⁸ is hydrogen. Insome embodiments, R⁷ is C₁₋₁₀ aliphatic or a substituted aliphatic groupof the formula —Z^(a)R¹⁸, —Z^(b)R¹⁹, or —Z^(a)R²⁰; R¹⁰ is C₂₋₁₀aliphatic or a substituted aliphatic group of the formula —Z^(a)R¹⁸,—Z^(b)R¹⁹, or —Z^(a)R²⁰; and R¹¹ is C₂₋₁₀ aliphatic or a substitutedaliphatic group of the formula —Z^(a)R¹⁸, —Z^(b)R¹⁹, —Z^(a)R²⁰. Thevariables Z^(a), Z^(b), R¹⁸, R¹⁹, and R²⁰ have the values describedbelow.

Z^(a) is an optionally substituted C₁₋₆ alkylene chain, wherein thealkylene chain is optionally interrupted by —C(R¹³)═C(R¹³)—, —C≡C—, —O—,—S—, —N(R¹³)—, —N(R¹³)C(O)—, —N(R¹³)CO₂—, —C(O)N(R¹³)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—, —S(O)₂—, —N(R¹³)S(O)₂—,—S(O)₂N(R¹³)—. In some embodiments, Z^(a) is optionally substituted withone to four R^(x) or R^(y), wherein R^(x) and R^(y) are as defined abovefor formula (VI). Preferably, Z^(a) is substituted with zero, one, ortwo substituents independently selected from the group consisting of —F,—OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃ alkyl), —C₁₋₃ aliphatic, —C₁₋₃fluoroaliphatic, and optionally substituted aryl. In certain particularembodiments, Z^(a) is a C₁₋₄ alkylene chain which is optionallysubstituted with zero, one or two groups selected from the groupconsisting of —F, —OH, C₁₋₃ aliphatic and optionally substituted aryl.

Z^(b) is an optionally substituted C₂₋₆ alkylene chain, wherein thealkylene chain is optionally interrupted by —C(R¹³)═C(R¹³)—, —C≡C—, —O—,—S—, —N(R¹³)—, —N(R¹³)C(O)—, —N(R¹³)CO₂—, —C(O)N(R¹³)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—, —S(O)₂—, —N(R¹³)S(O)₂—,—S(O)₂N(R¹³)—. In some embodiments, Z^(b) is optionally substituted withone to four R^(x) or R^(y), wherein R^(x) and R^(y) are as defined abovefor formula (VI). Preferably, Z^(b) is substituted with zero; one, ortwo substituents independently selected from the group consisting of —F,—OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃ alkyl), —C₁₋₃ aliphatic, —C₁₋₃fluoroaliphatic, and optionally substituted aryl. In certain particularembodiments, Z^(b) is a C₂₋₄ alkylene chain which is optionallysubstituted with zero, one or two groups selected from the groupconsisting of —F, —OH, C₁₋₃ aliphatic and optionally substituted aryl.

R¹⁸ is an optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic group.

R¹⁹ is —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂,—C(R¹⁴)═N—OR¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, or —C(═NR¹⁶)—OR¹⁴.

R²⁰ is halo, —NO₂, —CN, —OR¹⁴, SR¹⁵—, —N(R¹⁶)₂, —N(R¹⁶)C(O)R¹⁵,—N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴,—N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵, or —N(R¹⁶)SO₂—N(R¹⁶)₂.

One embodiment of the invention relates to a compound of formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:

Ring E is a mono- or bicyclic aryl, heteroaryl, heterocyclyl, orcycloaliphatic group;

W² is —O—, —S—, or —N(R⁸)—;

Z^(a) is an optionally substituted C₁₋₆ alkylene chain, wherein thealkylene chain is optionally interrupted by —C(R¹³)═C(R¹³)—, —C≡C—, —O—,—S—, —N(R¹³)—, —N(R¹³)C(O)—, —N(R¹³)CO₂—, —C(O)N(R¹³)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—, —S(O)₂—, —N(R¹³)S(O)₂—,—S(O)₂N(R¹³)—; and

the variables Q, X, Y, R², R^(3a), R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁸,and m have the values and preferred values described above for formulae(I) and (I-A).

In some such embodiments, Ring E is an optionally substituted furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydro-quinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, and benzodioxolyl rings. In certain preferredembodiments, Ring E is an optionally substituted phenyl, naphthyl,indanyl, furanyl, thienyl, pyrrolyl, pyrrolidinyl, isoxazolyl,pyrazolyl, piperidinyl, piperazinyl, or morpholinyl ring.

Suitable substituents for Ring E include those described generally abovefor substituted aryl, heteroaryl, or heterocyclyl groups. Eachsubstitutable ring nitrogen atom in Ring E is unsubstituted orsubstituted, preferably with —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —CO₂R¹⁴, —SO₂R¹⁵,—SO₂N(R¹⁶)₂, or an optionally substituted aliphatic. Substitutable ringcarbon atoms in Ring E preferably are substituted with zero to four,preferably zero to two substituents independently selected from thegroup consisting of C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, halo,—R^(a18), —R^(b18), —Z¹⁸—R^(a18), and —Z¹⁸—R^(b18). The variables Z¹⁸,R^(a18), and R^(b18) have the values described below.

Z¹⁸ is an optionally substituted C₁₋₆ alkylene chain, wherein thealkylene chain optionally is interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—,—S—, —S(O)—, —S(O)₂—, —SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—,—NR^(15c)(O)N(R¹⁵)—, —N(R¹⁵)CO₂—, —N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—,—CO₂—, —OC(O)—, —OC(O)O—, or —OC(O)N(R¹⁵)—, and wherein Z¹⁸ or a portionthereof optionally forms part of a 3-7 membered ring. In someembodiments, Z¹⁸ is a C₁₋₆ or C₁₋₄ alkylene chain optionally substitutedwith one or two R^(x) or R^(y), wherein R^(x) and R^(y) have the valuesand preferred values described above.

Each R^(a18) independently is an optionally substituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic ring.

Each R^(b18) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂. In someembodiments, each R^(b18) independently is —CN, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴—C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —C(O)N(R⁴)₂, —CO₂R⁵, or —OR⁵.

In some embodiments, the substitutable ring carbon atoms in Ring E aresubstituted with zero, one, or two substituents independently selectedfrom the group consisting of halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃alkyl), —C₁₋₃ aliphatic, —C₁₋₃ fluoroaliphatic, —O(C₁₋₃fluoroaliphatic), optionally substituted aryl, and optionallysubstituted heteroaryl. Preferred halo substituents on Ring E include Fand Cl.

In some embodiments, the invention relates to a compound of formula(VIII), wherein R⁸ is hydrogen, Z^(a) is C₁₋₃ alkylene, and Ring E is anoptionally substituted phenyl, naphthyl, indanyl, furanyl, thienyl,pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, piperazinyl, pyrazinyl,morpholinyl, benzothiophenyl, or benzodioxolyl ring. In some suchembodiments, the substitutable ring carbon atoms in Ring E aresubstituted with zero, one, or two substituents independently selectedfrom the group consisting of fluoro, chloro, —OH, -methoxy, —CN, —O(C₁₋₃alkyl),-trifluoromethyl, and —C₁₋₃ fluoroaliphatic.

Subgenus definitions for R¹, R², R^(3a), R^(3b), R^(3c), R^(3d), R⁴, andR⁵ described for formulae (I) and (I-A)also apply to formulae(II)-(VIII). Compounds embodying any combination of the preferred valuesfor the variables described herein are within the scope of the presentinvention.

Representative examples of compounds of formula (I-A)are shown in Table1.

TABLE 1 E1 activating enzyme inhibitors I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

The compounds in Table 1 above may also be identified by the followingchemical names:

Chemical Name

-   I-1:    ((2R,3S,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-hydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-2:    ((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-3:    ((2R,3S,4R,5R)-5-{2-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-4:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-5:    {(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methyl    sulfamate-   I-6:    {(2R,3S,4R,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-7:    ((2R,3S,4R,5R)-5-{6-[(cyclohexylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-8:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-thienylmethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-9:    ((2R,3S,4R,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-10:    ((2R,3S,4R,5R)-5-{6-[(4-chlorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-11:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(3-methoxybenzyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-12:    {(2R,3S,4R,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methyl    sulfamate-   I-13:    N-{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide-   I-14:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-15:    N-[((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide-   I-16:    ((2R,3S,4R,5R)-5-{6-[(4-chlorophenyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-17:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-phenylethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-18:    ((2R,3S,4R,5R)-5-{2-amino-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-19:    N-({(2R,3S,4R,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methyl)sulfamide-   I-20:    N-{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1S)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide-   I-21:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxyethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-22:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(5-methylpyrazin-2-yl)methyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-23:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1S)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-24:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1R)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-25:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl    sulfamate-   I-26:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(piperidin-4-ylmethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-27:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxybenzyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-28:    [(2R,3S,4R,5R)-5-(6-{[2-(4-benzylpiperazin-1-yl)ethyl]amino}-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl    sulfamate-   I-29:    ((1R,2R,3S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,3-dihydroxycyclopentyl)methyl    sulfamate-   I-30:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[4-(trifluoromethoxy)benzyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-31:    2-((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide-   I-32:    2-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]ethanesulfonamide-   I-33:    N-[((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(3-methoxybenzyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl]sulfamide-   I-34:    N-[((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-phenoxyethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl]sulfamide-   I-35:    N-[((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxyethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl]sulfamide-   I-36:    N-{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(5-methylpyrazin-2-yl)methyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide-   I-37:    N-[((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-thienylmethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl]sulfamide-   I-38:    N-{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1-methyl-1H-pyrazol-4-yl)methyl]-amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide-   I-39:    N-[((2R,3S,4R,5R)-5-{6-[(1,3-benzodioxol-5-ylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide-   I-40:    N-[((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(4-methoxybenzyl)sulfanyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide-   I-41:    {(2R,3S,4R,5R)-5-[6-(4-fluorobenzyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methyl    sulfamate-   I-42:    N-[((2R,3S,4R,5R)-5-{6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide-   I-43:    N-[((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl]sulfamide-   I-44: N-[((2R,3S,4R,5R)-5-{6-[(1-benzo    thien-3-ylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide-   I-45:    N-{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(1R)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide-   I-46:    N-[((2R,3S,4R,5R)-5-{6-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide-   I-47:    ((2R,3S,4R,5R)-5-{6-[(4-fluorobenzoyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-48:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(phenylsulfonyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-49:    2-((2R,3S,4R,5R)-5-{6-[(3,5-difluorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide-   I-50:    2-((2R,3S,4R,5R)-5-{6-[(4-chlorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide-   I-51:    2-((2R,3S,4R,5R)-5-{6-[(diphenylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide-   I-52:    2-{(2R,3S,4R,5R)-5-[6-(bicyclo[2.2.1]hept-2-ylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}ethanesulfonamide-   I-53:    ((2S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-hydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-54:    ((2R,3R,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methyl    sulfamate-   I-55:    ((2R,3R,4R,5R)-5-(6-((S)-2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methyl    sulfamate-   I-56:    ((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-57:    ((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[3-(trifluoromethyl)phenyl]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-58:    (R)-1-((2S,3S,4R,5R)-5-(6-((S)-2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)ethyl    sulfamate-   I-59:    {(2R,3S,4R,5R)-5-[6-phenethyl-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-60:    (2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-[6-((S)-indan-1-ylamino)-purin-9-yl]-tetrahydro-furan-2-ylmethyl-sulfamate-   I-61:    ((2R,3R,4S,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methyl    sulfamate-   I-62:    [(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydro    furan-2-yl]-methyl sulfamate-   I-63:    ((2R,3S,4R,5R)-5-{6-[(1,3-benzodioxol-5-ylmethyl)amino}-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl)methyl-sulfamate-   I-64:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-pyrrolidin-1-ylethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl-sulfamate-   I-65:    ((2R,3S,4R,5R)-5-{6-[(4-fluorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl-sulfamate-   I-66:    {(2R,3S,4R,5R)-5-[6-(3,5-Dimethylisoxazol-4-yl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-67:    ((2R,3S,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-68:    N-{[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(2R)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}-sulfamide-   I-69:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(E)-2-phenylvinyl]-9H-purin-9-yl}tetrahydro-furan-2-yl)methyl    sulfamate-   I-70:    [(2R,3R,4S,5R)-5-(6-ethyl-9H-purin-9-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl]methyl    sulfamate-   I-71:    ((2R,3S,4R,5R)-5-{6-[(2-chlorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-72:    N-({(2R,3R,4S,5R)-5-[6-(2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl]-4-fluoro-3-hydroxytetrahydrofuran-2-yl}methyl)sulfamide-   I-73:    [(2R,3R,4S,5R)-3-hydroxy-5-(6-isobutyl-9H-purin-9-yl)-4-methoxytetrahydro-furan-2-yl]methyl    sulfamate-   I-74:    {(2R,3S,4R,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-4-hydroxy-3-methoxytetrahydrofuran-2-yl}methyl    sulfamate-   I-75:    {(2R,3R,4R,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-4-fluoro-3-hydroxytetrahydro-furan-2-yl}methyl    sulfamate-   I-76:    N-({(2R,3R,4R,5R)-5-[6-(2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl]-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl}methyl)sulfamide-   I-77:    2-((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxy-2,3-dihydro-1H-inden-1-yl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)ethanesulfonamide-   I-78:    [(2R,3S,4R,5R)-5-(2-chloro-6-isobutyl-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]methyl    sulfamate-   I-79:    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[6-(2-phenylethyl)-9H-purin-9-yl]cyclopentyl}-methyl    sulfamate-   I-80:    [(1R,2S,4R)-2-hydroxy-4-(6-methyl-9H-purin-9-yl)cyclopentyl]methyl    sulfamate-   I-81:    2-[(1R,2S,4R)-2-hydroxy-4-(6-isobutyl-9H-purin-9-yl)cyclopentyl]-ethanesulfonamide-   I-82:    2-[(1R,2S,4R)-2-hydroxy-4-(6-isobutyl-9H-purin-9-yl)cyclopentyl]-ethanesulfonamide-   I-83:    N-({(1R,2R,3S,4R)-4-[6-(2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl]-2,3-dihydroxy-3-methylcyclopentyl}methyl)sulfamide-   I-84:    {(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(2-phenylethyl)-7H-pyrrolo[2,3-c]pyrimidin-7-yl]tetrahydrofuran-2-yl}methyl    sulfamate-   I-85:    {(1R,2R,3S,4R)-2,3-dihydroxy-3-methyl-4-[6-(2-phenylethyl)-9H-purin-9-yl]-cyclopentyl}methyl    sulfamate-   I-86:    N-({(2R,3S,4R,5R)-5-[4-(2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl)sulfamide-   I-87:    N-[((1R,2R,3S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,3-dihydroxycyclopentyl)methyl]sulfamide-   I-88:    ((2R,3S,4R,5R)-5-{6-[(3-fluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-89:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-trifluoromethylphenyl)ethynyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl    sulfamate-   I-90:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxyphenyl)ethynyl]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl    sulfamate-   I-91:    ((2R,3S,4R,5R)-5-{6-[(4-chlorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-92:    {(2R,3S,5R)-3-hydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}-methyl    sulfamate-   I-93:    [(2R,3S,5R)-3-hydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-94:    {(2R,3S,4R,5R)-5-[6-(2-furyl)-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl]-methyl    sulfamate-   I-95:    {(2R,3S,4R,5R)-5-[6-(cyclopropylethynyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-96:    [(1R,2R,3S,4R)-2,3-dihydroxy-4-(6-propyl-9H-purin-9-yl)cyclopentyl]methyl    sulfamate-   I-97:    [(1R,2R,3S,4R)-2,3-dihydroxy-4-(6-isobutyl-9H-purin-9-yl)cyclopentyl]methyl    sulfamate-   I-98:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-isobutyl-9H-purin-9-yl)tetrahydrofuran-2-yl]-methyl    sulfamate-   I-99:    [(2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-3-hydroxy-4-methoxytetrahydrofuran-2-yl]methyl    sulfamate-   I-100:    2-((2R,3S,4R,5R)-5-{6-[(3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide-   I-101:    ((2R,3S,4R,5R)-5-{6-[(4-bromophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-102:    {(2R,3S,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3-hydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-103:    ((2R,3S,4R,5R)-5-{6-[(3-bromophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-104:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-methyl-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-105:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(pyridin-3-ylcarbonyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-106:    [(2R,3S,5R)-5-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-3-hydroxytetrahydrofuran-2-yl]methyl    sulfamate-   I-107:    ((2R,3S,4R,5R)-5-{6-[(4-fluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-108:    ((2R,3S,4R,5R)-5-{6-[(anilinocarbonyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-109:    {(1R,2S,4R)-2-hydroxy-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentyl}methyl    sulfamate-   I-110:    ((2R,3S,4R,5R)-5-{6-[(2,4-difluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-111:    {(2R,3S,4R,5R)-5-[6-(2,3-dihydro-1H-inden-2-ylmethyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-112:    ((2R,3S,4R,5R)-5-{6-[(4-bromobenzoyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-113:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[2-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-114:    [(2R,3S,4R,5R)-5-(6-cyclopropyl-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl    sulfamate-   I-115:    N-({(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methyl)sulfamide-   I-116:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(2-methoxybenzoyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-117:    {(2R,3S,5R)-3-hydroxy-5-[5-iodo-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-2-yl}methyl    sulfamate-   I-118: [(2R,3S,5R)-3-hydroxy-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)    tetrahydrofuran-2-yl]methyl sulfamate-   I-119:    ((2R,3S,4R,5R)-5-{6-[(4-chlorobenzoyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-120:    ((2R,3S,4R,5R)-5-{6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-121:    ((2R,3R,4S,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-122:    {(2R,3S,4R,5R)-5-[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-123:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(4-methoxyphenyl)ethynyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl    sulfamate-   I-124:    {(2R,3S,5R)-5-[5-ethyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-125:    [(2R,3S,4R,5R)-5-(6-{[(3,5-difluorobenzoyl)amino]methyl}-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl    sulfamate-   I-126:    N-[((2R,3S,4R,5R)-5-{6-[(4-fluorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide-   I-127:    ((1R,2S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-hydroxycyclopentyl)methyl    sulfamate-   I-128:    {(2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-129:    ((2R,3S,4R,5R)-5-{6-[(benzoylamino)methyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-130:    ((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-131:    {(2R,3S,5R)-5-[5-[3-(diethylamino)prop-1-yn-1-yl]-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-132:    [(2R,3S,4R,5R)-5-(6-ethyl-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl    sulfamate-   I-133:    [(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxytetrahydro-furan-2-yl]methyl    sulfamate-   I-134:    ((2R,3S,4R,5R)-5-{6-[(3-chlorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-135:    {(2R,3S,5R)-5-[5-ethynyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-136:    ((2R,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-137:    {(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methoxyethyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methyl    sulfamate-   I-138:    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentyl}methyl    sulfamate-   I-139:    ((2R,3S,4R,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-d]pyridazin-1-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-140:    ((2R,3S,4R,5R)-5-{6-[(2-bromophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-141:    ((1R,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl    sulfamate-   I-142:    [(2R,3S,5R)-3-hydroxy-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-143:    {(2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-hydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-144:    [(2R,3S,5R)-3-hydroxy-5-(4-methoxy-7H-pyrrolo[2,3-c]pyrimidin-7-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-145:    [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[3-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl    sulfamate-   I-146:    ((2R,3S,4R,5R)-5-{6-[(3,5-difluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-147:    {(2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-[6-(2-phenylethyl)-9H-purin-9-yl]-tetrahydrofuran-2-yl}methyl    sulfamate-   I-148:    {(2R,3S,4R,5R)-5-[6-({2-[(acetylamino)methyl]benzyl}amino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methyl    sulfamate-   I-149:    ((2R,3S,4R,5R)-5-{-4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-c]-pyridin-1-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl    sulfamate-   I-150:    ((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxybenzoyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl    sulfamate-   I-151:    {(2R,3S,5R)-3-methoxy-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methyl    sulfamate-   I-152:    ((2R,3S,4R,5R)-5-{6-[(2-fluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl    sulfamate

General Synthetic Methodology

The compounds of this invention may be prepared by methods known tothose skilled in the art for analogous compounds, as illustrated by thegeneral schemes below, and by reference to the preparative examplesshown below. In particular, the compounds of the invention may beprepared by various methods known in the art of organic chemistry andnucleoside and nucleotide analogue synthesis in particular. For example,general reviews of the preparation of nucleoside and nucleotideanalogues are included in “Chemistry of Nucleosides and Nucleotides,”Ed. L. B. Townsend, Plenum Press, 1991; and S. Simons, “NucleosideMimetics Their Chemistry and Biological Properties,” Gordon and BreachScience Publishers, 2001.

Scheme 1 above shows a general route to compounds of formula (IV-A).Starting materials for the syntheses are either available fromcommercial sources, are known, or may be prepared by routine techniquesknown in the art. Compound i (Y═O: commercially available; Y═C: Shealy,Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-308) is convertedto compound II or iii by treatment with 2,2-dimethoxypropane in thepresence of an acid such as para-toluenesulfonic acid in an appropriatesolvent, such as acetone (a). It will be understood that alternativeprotecting group strategies facilitating the derivatization of theprimary alcohol (5′-position) of nucleosides may be utilized, and areknown to those of ordinary skill in the art and taught by Greene‘Protective Groups in Organic Synthesis”, John Wiley and Sons, 3rdEdition, 1999.

Following introduction of the protecting group, displacement of aleaving group from the 6-position of a purine, by for example an aminenucleophile, is known and yields nucleoside analogues derivatized at the6-position. Procedures have been adapted from those described by Golding(J. Chem. Soc. Perkin Trans 1, 1997, 185). For example, compound II isproduced by treatment with a primary amine, in the presence of atertiary amine such as triethylamine and an appropriate solvent such asEtOH or water under conditions such as reflux or microwave (b). CompoundIv may be produced by treatment of resulting compound ii withchlorosulfonamide in an appropriate solvent such as acetonitrile and abase such as triethylamine in an appropriate solvent such asN,N-dimethylformamide(c) followed by treatment with an acid, such astrifluoroacetic acid in an appropriate solvent such as water (d).

Alternatively, sulfamoylation can be effected prior to reaction with anamine nucleophile. Thus, following introduction of the protecting group,sulfamoylation of the unprotected alcohol can be achieved by reactionwith chlorosulfonamide in an appropriate solvent such as acetonitrileand a base such as triethylamine in an appropriate solvent such asN,N-dimethylformamide(c) to afford compound iii. Compound Iv may then beproduced by addition of a primary amine to a solution of compound iii inan appropriate solvent, such as ethanol, in the presence of anappropriate base, such as quinuclidine(e), followed by treatment with anwith an acid, such as trifluoroacetic acid and an appropriate solventsuch as water (d).

Compounds of formula (I-A) wherein R¹ is an amide or sulfonamidesubstituent can be prepared by reaction of the 6-amino group of asuitably protected adenosine derivative with an appropriately activatedcarboxylic acid or sulfonyl chloride.

Some embodiments involve derivatization of the ribose moiety, inaddition to sulfamoylation at the 5′-position. Examples include2′-C-branched ribonucleosides, deoxy derivatives, fluoro-deoxyderivatives and O-alkylated compounds. Such compounds can be prepared bycoupling a suitably protected ribose derivative to a purine base.Methods for effecting this coupling reaction are known to those ofordinary skill in the art, for example the method taught by VorbruggenH. et. al. “Handbook of Nucleoside Synthesis”, John Wiley and Sons,2001. Suitable protecting groups are also known to those of ordinaryskill in the art, and may be found described for example, in Greene“Protective Groups in Organic Synthesis”, John Wiley and Sons, 3rdEdition, 1999. In a particular embodiment, 2′-C-methylated derivativescan be prepared following the procedures described in Franchetti (J.Med. Chem. 1998, 41, 1708) and Wolfe (J. Org. Chem. 1997, 62, 1754).

Some embodiments involve derivatization of the purine moiety, inaddition to sulfamoylation at the 5′-position. Examples include ringsA-ii, A-iii, A-iv, A-v, A-vi, and A-vii. Such compounds can be preparedby coupling a suitably protected ribose derivative to these bases.Methods for effecting this coupling reaction are known to those ofordinary skill in the art, for example the method taught by VorbruggenH. et. al. “Handbook of Nucleoside Synthesis”, John Wiley and Sons,2001. Suitable protecting groups are also known to those of ordinaryskill in the art, and may be found described for example, in Greene“Protective Groups in Organic Synthesis”, John Wiley and Sons, 3^(rd)Edition, 1999. In a particular embodiment, 2′-deoxy-ribose analogs canbe prepared by coupling1-α-chloro-2-deoxy-3,5-bis(p-toluoyl)-α-D-ribofuranosyl chloride with avariety of nucleoside base analogs following the procedures described inRobins (J. Am. Chem. Soc 1984, 106, 6379).

In an analogous fashion to the preparation of sulfamate derivatives ofcompound (IV-A) described in scheme 1, sulfamide derivatives can beprepared at the 5′-position. Scheme 2 above shows a general route tosynthesis of compounds of formula (IIA).

For example, compound v, prepared according to step (a) of scheme Iabove, can be treated with tert-butyl (aminosulfonyl) carbamate(compound xxi), in the presence of triphenylphosphine and anazodicarboxylate(g) to form the sulfamide compound vi. Sulfamidedeprotection by treatment with an acid such as trifluoroacetic acid inan appropriate solvent, such as dichloromethane(h), followed bytreatment with a primary amine in the presence of a tertiary amine, suchas triethylamine and an appropriate solvent such as EtOH or water underconditions such as reflux or microwave(b) then affords compound vii.Compound vii is then treated with an acid, such as trifluoroacetic acidin an appropriate solvent such as water (d) to form compound viii.

Furthermore, analogous to the preparation of sulfamate derivatives ofcompound (IV-A) described in scheme I, sulfonamide derivatives can beprepared at the 5′-position. Scheme 3 above shows a general route tosynthesis of compounds of formula (IIIA)

Thus, oxidation of the alcohol of compound v (prepared as in step (a) ofScheme 1) with a standard oxidizing agent, such as Dess-Martinperiodinane, and dichloromethane (j) affords aldehyde ix. Treatment ofcompound ix with a phosphoryl methane sulfonic acid ester (xxii) andn-butyllithium in an appropriate solvent, such as tetrahydrofuran(k)produces the alkene compound x. Reduction and subsequent functionalgroup interconversion of compound x, for example under steps, (l), (m),(n), (p), (r), and (d), gives the sulfonamide compound xi.

Scheme 4 above shows a general synthesis of compounds of formula (IV-A),wherein R¹ is an optionally substituted aliphatic, aryl or heteroarylgroup. Compound xii can be prepared by reaction of compound v (preparedas described above in Scheme 2) with pyridine, dimethylaminopyridine andacetic anhydride in methylene chloride.

Compounds xiii can be produced by introduction of a variety of alkyl oraryl functionality at the 6-position of the purine ring through apalladium catalyzed coupling with a suitable organometallic reagent,aryl boronic acid, or alkyne (e.g., Scheme 4 step (s)). Syntheticprocedures are known in the art and can be adapted as applicable. Forexample procedures described herein were adapted from those describedin, e.g., Lakshman (J. Am. Chem. Soc. 2001, 123, 7779); Hocek (Collect.Czech. Commun., 2001, 66, 483; Robins (Org. Lett., 2004, 6, 2917). For areview of palladium assisted routes to nucleoside analogues seeAgrofoglio (Chem. Rev., 2003, 103, 1875).

Treatment of resulting compound xiii with ammonia in methanol, followedby steps (c) and (d) as described above as in Scheme 1, results insynthesis of the 5′-sulfamoylated compound xv.

While Scheme 4 depicts synthesis of formula (IV-A), procedures may bereadily adapted for synthesis of compounds of formulae (II-A), (IIIA),(II-B), (III-B), and (IV-B) using analogous procedures providedthroughout the general schemes and examples, as well as application ofalternate synthesis routes known in the art.

One of ordinary skill in the art will recognize that numerous variationsin reaction conditions including variations in solvent, reagents,catalysts, reaction temperatures and times are possible for each of thereactions described. Alternative synthetic routes are also possible.

Uses of Compounds of the Invention

The compounds of this invention are useful inhibitors of E1 enzymeactivity. In particular, the compounds are designed to be inhibitors ofNAE, UAE, and/or SAE. Inhibitors are meant to include compounds whichreduce the promoting effects of E1 enzymes in ubl conjugation to targetproteins (e.g., reduction of ubiquitination, neddylation, sumoylation),reduce intracellular signaling mediated by ubl conjugation, and/orreduce proteolysis mediated by ubl conjugation (e.g., inhibition ofcullin-dependent ubiquitination and proteolysis (e.g., theubiquitin-proteasome pathway)). Thus, the compounds of this inventionmay be assayed for their ability to inhibit the E1 enzyme in vitro or invivo, or in cells or animal models according to methods provided infurther detail herein, or methods known in the art. The compounds may beassessed for their ability to bind or mediate E1 enzyme activitydirectly. Alternatively, the activity of compounds may be assessedthrough indirect cellular assays, or assays of downstream effects of E1activation to assess inhibition of downstream effects of E1 inhibition(e.g., inhibition of cullin-dependent ubiquitination and proteolysis).For example, activity may be assessed by detection of ubl-conjugatedsubstrates (e.g., ubl-conjugated E2s, neddylated cullins, ubiquitinatedsubstrates, sumoylated substrates); detection of downstream proteinsubstrate stabilization (e.g., stabilization of p27, stabilization ofIκB); detection of inhibition of UPP activity; detection of downstreameffects of protein E1 inhibition and substrate stabilization (e.g.,reporter assays, e.g., NFκB reporter assays, p27 reporter assays).Assays for assessing activities are described below in the Experimentalsection and/or are known in the art.

One embodiment of this invention relates to a composition comprising acompound of this invention or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. It will beappreciated that the compounds of this invention may be derivatized atfunctional groups to provide prodrug derivatives which are capable ofconversion back to the parent compounds in vivo. Examples of suchprodrugs include the physiologically acceptable and metabolically labileester derivatives, such as methoxymethyl esters, methylthiomethylesters, or pivaloyloxymethyl esters derived from a hydroxyl group of thecompound or a carbamoyl moiety derived from an amino group of thecompound. Additionally, any physiologically acceptable equivalents ofthe present compounds, similar to the metabolically labile esters orcarbamates, which are capable of producing the parent compoundsdescribed herein in vivo, are within the scope of this invention.

If pharmaceutically acceptable salts of the compounds of the inventionare utilized in these compositions, the salts preferably are derivedfrom inorganic or organic acids and bases. For reviews of suitablesalts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) andRemington: The Science and Practice of Pharmacy, 20th Ed., ed. A.Gennaro, Lippincott Williams & Wilkins, 2000.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine,and salts with amino acids such as arginine, lysine, and so forth.

In certain particular embodiments, the invention relates to a baseaddition salt of a compound of formula I formed by deprotonation of thesulfamate (X═O) moiety, the sulfamide (X═NH) moiety, or the sulfonamide(X═CH₂) moiety, as applicable. In some such embodiments, the inventionrelates to a sodium or potassium salt of a compound of formula I.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The term “pharmaceutically acceptable carrier” is used herein to referto a material that is compatible with a recipient subject, preferably amammal, more preferably a human, and is suitable for delivering anactive agent to the target site without terminating the activity of theagent. The toxicity or adverse effects, if any, associated with thecarrier preferably are commensurate with a reasonable risk/benefit ratiofor the intended use of the active agent.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, solubilizing agents,bioavailability modifiers and combinations of these.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a liquid, such as, but not limited to, an oil, water, analcohol, and combinations of these. Solubilizing agents such ascyclodextrins may be included. Pharmaceutically suitable surfactants,suspending agents, or emulsifying agents, may be added for oral orparenteral administration. Suspensions may include oils, such as but notlimited to, peanut oil, sesame oil, cottonseed oil, corn oil and oliveoil. Suspension preparation may also contain esters of fatty acids suchas ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates and carbonates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intraperitoneal, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intravenously, or subcutaneously.The formulations of the invention may be designed to be short-acting,fast-releasing, or long-acting. Still further, compounds can beadministered in a local rather than systemic means, such asadministration (e.g., by injection) at a tumor site.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The pharmaceutical compositions of this invention are particularlyuseful in therapeutic applications relating to disorders as describedherein (e.g., proliferation disorders, e.g., cancers, inflammatory,neurodegenerative disorders). Preferably, the composition is formulatedfor administration to a patient having or at risk of developing orexperiencing a recurrence of the relevant disorder being treated. Theterm “patient”, as used herein, means an animal, preferably a mammal,more preferably a human. Preferred pharmaceutical compositions of theinvention are those formulated for oral, intravenous, or subcutaneousadministration. However, any of the above dosage forms containing atherapeutically effective amount of a compound of the invention are wellwithin the bounds of routine experimentation and therefore, well withinthe scope of the instant invention. In certain embodiments, thepharmaceutical composition of the invention may further comprise anothertherapeutic agent Preferably, such other therapeutic agent is onenormally administered to patients with the disorder, disease orcondition being treated.

By “therapeutically effective amount” is meant an amount of compound orcomposition sufficient, upon single or multiple dose administration, tocause a detectable decrease in E1 enzyme activity and/or the severity ofthe disorder or disease state being treated. “Therapeutically effectiveamount” is also intended to include an amount sufficient to treat acell, prolong or prevent advancement of the disorder or disease statebeing treated (e.g., prevent additional tumor growth of a cancer,prevent additional inflammatory response), ameliorate, alleviate,relieve, or improve a subject's symptoms of the a disorder beyond thatexpected in the absence of such treatment. The amount of E1 enzymeinhibitor required will depend on the particular compound of thecomposition given, the type of disorder being treated, the route ofadministration, and the length of time required to treat the disorder.It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, and diet of the patient, time ofadministration, rate of excretion, drug combinations, the judgment ofthe treating physician, and the severity of the particular disease beingtreated. In certain aspects where the inhibitor is administered incombination with another agent, the amount of additional therapeuticagent present in a composition of this invention typically will be nomore than the amount that would normally be administered in acomposition comprising that therapeutic agent as the only active agent.Preferably, the amount of additional therapeutic agent will range fromabout 50% to about 100% of the amount normally present in a compositioncomprising that agent as the only therapeutically active agent.

One embodiment of the invention relates to a method of inhibiting ordecreasing E1 enzyme activity in a sample comprising contacting thesample with a compound of this invention, or composition comprising acompound of the invention. The sample, as used herein, includes, withoutlimitation, sample comprising purified or partially purified E1 enzyme,cultured cells or extracts of cell cultures; biopsied cells or fluidobtained from a mammal, or extracts thereof; and body fluid (e.g.,blood, serum, saliva, urine, feces, semen, tears) or extracts thereof.Inhibition of E1 enzyme activity in a sample may be carried out in vitroor in vivo, in cellulo, or in situ.

In another embodiment, the invention provides a method for treating apatient having a disorder, a symptom of a disorder, at risk ofdeveloping or experiencing a recurrence of a disorder, comprisesadministering to the patient a compound or pharmaceutical compositionaccording to the invention. Treating can be to cure, heal, alleviate,relieve, alter, remedy, ameliorate, palliate, improve or affect thedisorder, the symptoms of the disorder or the predisposition toward thedisorder. While not wishing to be bound by theory, treating is believedto cause the inhibition of growth, ablation, or killing of a cell ortissue in vitro or in vivo, or otherwise reduce capacity of a cell ortissue (e.g., an aberrant cell, a diseased tissue) to mediate adisorder, e.g., a disorder as described herein (e.g., a proliferativedisorder, e.g., a cancer, inflammatory disorder). As used herein,“inhibiting the growth” or “inhibition of growth” of a cell or tissue(e.g., a proliferative cell, tumor tissue) refers to slowing,interrupting, arresting or stopping its growth and metastases and doesnot necessarily indicate a total elimination of growth.

Disease applications include those disorders in which inhibition of E1enzyme activity is detrimental to survival and/or expansion of diseasedcells or tissue (e.g., cells are sensitive to E1 inhibition; inhibitionof E1 activity disrupts disease mechanisms; reduction of E1 activitystabilizes protein which are inhibitors of disease mechanisms; reductionof E1 activity results in inhibition of proteins which are activators ofdisease mechanisms). Disease applications are also intended to includeany disorder, disease or condition which requires effective cullinand/or ubiquitination activity, which activity can be regulated bydiminishing E1 enzyme activity (e.g., NAE, UAE activity).

For example, methods of the invention are useful in treatment ofdisorders involving cellular proliferation, including, but not limitedto, disorders which require an effective cullin-dependent ubiquitinationand proteolysis pathway (e.g., the ubiquitin proteasome pathway) formaintenance and/or progression of the disease state. The methods of theinvention are useful in treatment of disorders mediated via proteins(e.g., NFκB activation, p27^(Kip) activation, p21^(WAF/CIP1) activation,p53 activation) which are regulated by E1 activity (e.g., NAE activity,UAE activity, SAE activity). Relevant disorders include proliferativedisorders, most notably cancers and inflammatory disorders (e.g.,rheumatoid arthritis, inflammatory bowel disease, asthma, chronicobstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g.,atopic dermatitis, psoriasis), vascular proliferative disorders (e.g.,atherosclerosis, restenosis) autoimmune diseases (e.g., multiplesclerosis, tissue and organ rejection)); as well as inflammationassociated with infection (e.g., immune responses), neurodegenerativedisorders (e.g., Alzheimer's disease, Parkinson's disease, motor neuronedisease, neuropathic pain, triplet repeat disorders, astrocytoma, andneurodegeneration as result of alcoholic liver disease), ischemic injury(e.g., stroke), and cachexia (e.g., accelerated muscle protein breakdownthat accompanies various physiological and pathological states, (e.g.,nerve injury, fasting, fever, acidosis, HIV infection, canceraffliction, and certain endocrinopathies)).

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes, but is not limited to, solid tumors and bloodbornetumors. The term “cancer” encompasses diseases of skin, tissues, organs,bone, cartilage, blood, and vessels. The term “cancer” furtherencompasses primary and metastatic cancers.

In some embodiments, the cancer is a solid tumor. Non-limiting examplesof solid tumors that can be treated by the methods of the inventioninclude pancreatic cancer; bladder cancer; colorectal cancer; breastcancer, including metastatic breast cancer; prostate cancer, includingandrogen-dependent and androgen-independent prostate cancer; renalcancer, including, e.g., metastatic renal cell carcinoma; hepatocellularcancer; lung cancer, including, e.g., non-small cell lung cancer(NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of thelung; ovarian cancer, including, e.g., progressive epithelial or primaryperitoneal cancer; cervical cancer; gastric cancer; esophageal cancer;head and neck cancer, including, e.g., squamous cell carcinoma of thehead and neck; melanoma; neuroendocrine cancer, including metastaticneuroendocrine tumors; brain tumors, including, e.g., glioma, anaplasticoligodendroglioma, adult glioblastoma multiforme, and adult anaplasticastrocytoma; bone cancer; and soft tissue sarcoma.

In some other embodiments, the cancer is a hematologic malignancy.Non-limiting examples of hematologic malignancy include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CIVIL and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the compound or composition of the invention isused to treat a patient having or at risk of developing or experiencinga recurrence in a cancer selected from the group consisting ofcolorectal cancer, ovarian cancer, lung cancer, breast cancer, gastriccancer, prostate cancer, and pancreatic cancer. In certain preferredembodiments, the cancer is selected from the group consisting of lungcancer, colorectal cancer, ovarian cancer and a hematologic cancer.

Depending on the particular disorder or condition to be treated, in someembodiments, the E1 enzyme inhibitor of the invention is administered inconjunction with additional therapeutic agent or agents. In someembodiments, the additional therapeutic agent(s) is one that is normallyadministered to patients with the disorder or condition being treated.As used herein, additional therapeutic agents that are normallyadministered to treat a particular disorder or condition are known as“appropriate for the disorder or condition being treated.”

The E1 inhibitor of the invention may be administered with the othertherapeutic agent in a single dosage form or as a separate dosage form.When administered as a separate dosage form, the other therapeutic agentmay be administered prior to, at the same time as, or followingadministration of the E1 inhibitor of the invention.

In some embodiments, the E1 enzyme inhibitor of the invention isadministered in conjunction with a therapeutic agent selected from thegroup consisting of cytotoxic agents, radiotherapy, and immunotherapyappropriate for treatment of proliferative disorders and cancer.Non-limiting examples of cytotoxic agents suitable for use incombination with the E1 enzyme inhibitors of the invention include:antimetabolites, including, e.g., capecitibine, gemcitabine,5-fluorouracil or 5-fluorouracil/leucovorin, fludarabine, cytarabine,mercaptopurine, thioguanine, pentostatin, and methotrexate;topoisomerase inhibitors, including, e.g., etoposide, teniposide,camptothecin, topotecan, irinotecan, doxorubicin, and daunorubicin;vinca alkaloids, including, e.g., vincristine and vinblastin; taxanes,including, e.g., paclitaxel and docetaxel; platinum agents, including,e.g., cisplatin, carboplatin, and oxaliplatin; antibiotics, including,e.g., actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin,idarubicin, doxorubicin and pegylated liposomal doxorubicin; alkylatingagents such as melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine, andcyclophosphamide; including, e.g., CC-5013 and CC-4047; protein tyrosinekinase inhibitors, including, e.g., imatinib mesylate and gefitinib;proteasome inhibitors, including, e.g., bortezomib, thalidomide andrelated analogs; antibodies, including, e.g., trastuzumab, rituximab,cetuximab, and bevacizumab; mitoxantrone; dexamethasone; prednisone; andtemozolomide.

Other examples of agents the inhibitors of the invention may be combinedwith include anti-inflammatory agents such as corticosteroids, TNFblockers, II-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporine,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, methotrexate, andsulfasalazine; antibacterial and antiviral agents; and agents forAlzheimer's treatment such as donepezil, galantamine, memantine andrivastigmine.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

EXAMPLES Abbreviations

-   AcCN acetonitrile-   AcOH acetic acid-   aq aqueous-   ATP adenosine triphosphate-   DIPEA diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DCM dichloromethane-   DMSO dimethylsulfoxide-   eq equivalents-   EtOAc ethyl acetate-   EtOH ethanol-   ES+ electrospray +ve mode-   ES− electrospray −ve mode-   FRET fluorescence resonance energy transfer-   h hours-   HPLC high pressure liquid chromatography-   LCMS liquid chromatography mass spectrum-   MeOH methanol-   MHz megahertz-   min minutes-   mL milliliter-   mM millimolar-   mm millimeter-   MS mass spectrum-   nM nanomolar-   NMR nuclear magnetic resonance-   pTsOH para-toluenesulfonic acid-   r.t. room temperature-   R.t. retention time-   s seconds-   SDS sodium dodecyl sulfate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran

The following analytical methods were utilized in the preparation andanalysis of the compounds as specified in the Examples below:

LCMS: compounds were analyzed on a Phenomenex Luna column [C18, 30×4.6mm, 5 μm], flow rate 2.5 mL/min.

-   -   Formic acid method: mobile phase A consisting of 5%        acetonitrile/water/0.1% formic acid and mobile phase B of 99%        acetonitrile/water/0.1% formic acid.    -   Ammonium acetate method: mobile phase A consisting of 1%        acetonitrile/10 mM ammonium acetate aqueous and mobile phase B        of 95% acetonitrile/10 mM ammonium acetate aqueous. The 5 min        cycle consisted of a gradient of 5% to 100% B in 3.5 min; 100% B        for 1 min; 100% B to 100% A in 0.1 min; then re-equilibration        with mobile phase A for 0.49 min.

NMR: proton spectra were recorded on a Bruker 300 or 400 MHz ultrashieldspectrometer. Chemical shifts are reported relative to methanol (δ3.31)or dimethyl sulfoxide (δ 2.50).

Microwave: All microwave reactions were carried out using a PersonalChemistry ‘Creator’ system operating a single mode cavity at 2450 MHzwith a maximum power of 300 W. The chemistry was carried out in sealedtubes with a capacity of 0.5 to 8 mL and a pressure cut out of 22 bar.

Example 1((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-2) Step a:[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl]methanol

6-Chloro-β-D-ribofuranosylpurine (8.17 g, 28.5 mmol), p-toluenesulfonicacid monohydrate (5.42 g, 28.5 mmol) and 2,2-dimethoxypropane (17.5 mL,142.5 mmol) were mixed in acetone (500 mL). The reaction mixture wasstirred at room temperature for 16 hours. Saturated aqueous NaHCO₃solution (400 mL) was then added and the mixture was evaporated underreduced pressure to remove most of the acetone. The remaining aqueousresidue was then extracted with chloroform(4×200 mL). The combinedorganics were dried over Na₂SO₄, and then evaporated to yield theproduct as a white amorphous solid (9.22 g, 99%).

LCMS: R.t. 1.22 min ES+327 (formic acid).

Step b:((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol

[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methanol(736 mg, 2.26 mmol), (S)-(+)-1-aminoindane (360 mg, 2.71 mmol) andtriethylamine(380 μL, 2.71 mmol) were added to ethanol (2.5 mL) and themixture was heated at 140° C. for 10 minutes using microwaveirradiation. The cooled mixture was diluted with diethyl ether (5 mL)and the precipitated product isolated by filtration. Further product wasisolated from the filtrates by evaporation, followed byrecrystallization from ethanol/ether. Total yield was 630 mg, 66%.

LCMS: R.t. 1.64 min ES+ 424 (formic acid).

Step c:((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate

A 2M solution of chlorosulfonamide in acetonitrile was prepared asfollows:

Formic acid (2.3 mL, 60 mmol) was added dropwise, with stirring toChlorosulfonyl isocyanate (5.2 mL, 60 mmol) under nitrogen at 0° C.After the addition was complete and the mixture had solidified,acetonitrile (30 mL) was added. The resulting solution was left to standunder a vented source of nitrogen overnight at room temperature.

((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(525 mg, 1.24 mmol) and triethylamine (260 μL, 1.86 mmol) were dissolvedin N,N-dimethylformamide (3 mL) under nitrogen. The solution was cooledto 0° C. and freshly prepared chlorosulfonamide solution (2M) (0.93 mL,1.86 mmol) was added dropwise. The mixture was stirred for 1 hour at 0°C., until complete by LCMS. The mixture was allowed to warm to roomtemperature, diluted with dichloromethane (20 mL) and the organic phasewas washed with brine (2×10 mL), water (10 mL) and evaporated to give acrude product, 445 mg (71%). This was used without further purification.

LCMS: R.t. 1.62 min ES+503 (formic acid).

Step d:((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-2)

((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (400 mg, 0.80 mmol) was dissolved in a preformed mixture oftrifluoroacetic acid (1.8 mL) and water (0.2 mL). The solution wasallowed to stand at room temperature for 10 minutes and evaporated todryness. This was twice evaporated from methanol and the residue waspurified by reverse phase HPLC to yield 248 mg (67%) of final compound.

LCMS: R.t. 1.27 min ES+463 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.31 (s, 1H), 8.28 (br, 1H), 8.16 (br, 1H),7.60 (s, 2H), 7.19 (m, 4H), 5.97 (m, 2H), 5.67 (br, 1H), 5.47 (br, 1H),4.63 (t, 1H, J=4.9 Hz), 4.22 (m, 4H), 3.01 (m, 1H), 2.83 (m, 1H), 2.10(br, 1H)

Example 2((2R,3S,4R,5R)-5-{6-[(4-chlorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxy-tetrahydrofuran-2-yl)methylsulfamate (I-10)

The title compound was prepared following the procedure described inExample 1, steps b-d, using 4-Chloro-benzylamine in step b.

LCMS: R.t. 1.23 min ES+ 471 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.34 (s, 1H), 8.21 (s, 1H), 7.35 (s, 4H),5.94 (d, 1H, J=5.3 Hz), 4.63 (m, 1H), 4.31-4.11 (m, 4H).

Example 3((2R,3S,4R,5R)-5-{6-[(cyclohexylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-7)

The title compound was prepared following the procedure described inExample 1, steps b-d, using cyclohexyl-methylamine in step b.

LCMS: R.t. 1.15 min ES+ 443 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.28 (s, 1H), 8.21 (s, 1H), 7.84 (br s,1H), 7.59 (s, 2H), 5.93 (d, 1H, J=5.3 Hz), 4.62 (m, 1H), 4.31-4.11 (m,4H), 1.68 (m, 6H), 1.15 (m, 3H), 0.94 (m, 2H).

Example 4((2R,3S,4R,5R)-5-{6-[(4-Chlorophenyl)amino]-9H-purin-9-yl}-3,4-dihydroxy-tetrahydrofuran-2-yl)methylsulfamate (I-16)

The title compound was prepared following the procedure described inExample 1, steps b-d, using 4-chloroaniline in step b.

LCMS: R.t. 1.39 min ES+ 457 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.47 (s, 1H), 8.40 (s, 1H), 7.98 (d, 2H,J=8.9 Hz), 7.34 (d, 2H, J=8.9 Hz), 5.97 (d, 1H, J=5.2 Hz), 4.62 (t, 1H,J=5.1 Hz), 4.21 (m, 4H).

Example 5((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-phenylethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methylsulfamate (I-17)

The title compound was prepared following the procedure described inExample 1, steps b-d, using phenethylamine in step b.

LCMS: R.t. 1.10 min ES+ 451 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.29 (s, 1H), 8.24 (s, 1H), 7.88 (br s,1H), 7.57 (s, 2H), 7.31-7.18 (m, 5H), 5.94 (d, 1H, J=5.3 Hz), 5.59 (d,1H, J=58 Hz), 5.42 (d, 1H, J=5.5 Hz), 4.61 (dd, 1H, J=5.5 Hz, J=11.0Hz), 4.30-4.11 (m, 4H), 3.71 (br s, 2H), 2.91 (t, 2H, J=8.2 Hz).

Example 6((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(3-methoxybenzyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl-sulfamate(I-11) Step a: Sulfamic acid6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxol4-ylmethyl ester

[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol(6.53 g, 20 mmol) and triethylamine (4.17 mL, 30 mmol) were dissolved inDMF (30 mL) under nitrogen and cooled on an ice bath. Chlorosulfonamidesolution (10 mL, 20 mmol) was then added over 5 minutes and the mixturestirred for 90 minutes. Two further portions of chlorosulfonamide (5 mL,10 mmol) were added with the reaction mixture stirred for a 60 minutesafter each addition. The mixture was then evaporated under vacuum at 50°C. and the residue was purified by column chromatography on silica (120g) using ethyl acetate gradient 0 to 100% in hexane to give the desiredproduct, as a foam (6.88 g, 85%).

Step b:1-[9-(2,2-Dimethyl-6-sulfamoyloxymethyl-tetrahydro-furo[3,4-d][1,3]-dioxol-4-yl)-9Hpurin-6-yl]-1-azonia-bicyclo[2.2.2]octanechloride

Quinuclidine (785 mg, 7.06 mmol) was dissolved in ethanol (39 mL) and1.5 mL (0.2716 mmol) of the solution was added to sulfamic acid6-(6-chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ylmethyl ester (100 mg, 0.246 mmol) in a 10 mL vial. The reaction vial wassealed and agitated for 1 hour, then evaporated to dryness to yieldcrude product, which was used directly in the next step.

Step c:((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(3-methoxybenzyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl-sulfamate(I-11)

3-Methoxybenzylamine (4.0 eq, 0.986 mmol) was dissolved in EtOH (1.5 mL)and added to the crude product described above (0.246 mmol). Thereaction mixture was agitated overnight, and then evaporated to dryness.The resulting residue was treated with 1 mL of TFA/water (9:1) for 20minutes. The solution was evaporated and the product purified bypreparative HPLC.

LCMS: R.t. 1.35 min, ES+ 467 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.36 (s, 1H), 8.25 (s, 1H), 7.23 (t, 1H,J=7.9 Hz), 6.95 (s, 2H), 6.81 (d, 1H, J=7.1 Hz), 5.98 (d, 1H, J=5.2 Hz),5.68 (br, 1H), 5.50 (br, 1H), 4.68 (dd, 2H, J=7.8 Hz, J=13.6 Hz), 4.26(m, 4H), 3.73 (s, 3H).

Example 7((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-thienylmethyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methyl-sulfamate(I-8)

The title compound was prepared as described in Example 6, step c, using2-methylaminothiophene.

LCMS: R.t. 1.31 min, ES+ 443 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.36 (s, 1H), 8.31 (s, 1H), 7.62 (s, 2H),7.36 (d, 1H, J=4.9 Hz), 7.05 (d, 1H, J=3.3 Hz), 6.96 (dd, 1H, J=3.5 Hz,J=5.0 Hz), 5.98 (d, 1H, J=5.3 Hz), 5.65 (d, 1H, J=5.9 Hz), 5.47 (d, 1H,J=5.3 Hz), 4.88 (br, 2H), 4.66 (m, 1H), 4.24 (m, 4H).

Example 8[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(5-methylpyrazin-2-yl)methyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl-sulfamate(I-22)

The title compound was prepared as described in Example 6, step c, using3-methyl-5-methylaminopyrazine

LCMS: R.t. 1.06 min, ES+ 453 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.50 (br, 2H), 8.40 (s, 1H), 8.26 (s, 1H),7.64 (s, 2H), 6.00 (d, 1H, J=5.3 Hz), 5.55 (br, 2H), 4.86 (br, 2H), 4.68(t, 1H, J=5.1 Hz), 4.27 (m, 4H), 2.49 (s, 3H).

Example 9[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1S)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl-sulfamate(I-23)

The title compound was prepared as described in Example 6, step c, using(S)-alpha-hydroxymethyl benzylamine.

LCMS: R.t. 1.19 min, ES+ 467 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 7.58 (br, 2H), 7.42 (d, 2H, J=7.6 Hz), 7.28(t, 1H, J=7.3 Hz), 7.19 (t, 1H, J=7.2 Hz), 5.93 (d, 1H, J=5.2 Hz), 5.62(br, 1H), 5.40 (br, 2H), 4.60 (q, 1H, J=7.0 Hz), 4.20 (m, 4H), 3.76 (td,2H, J=11.1 Hz, J=15.9 Hz).

Example 10[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1R)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl-sulfamate(I-24)

The title compound was prepared as described in Example 6, step c, using(R)-alpha-hydroxymethylbenzylamine

LCMS: R.t. 1.23 min, ES+ 467 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.38 (s, 1H), 8.20 (s, 1H), 8.09 (d, 1H,J=8.5 Hz), 7.61 (s, 2H), 7.46 (d, 2H, J=7.4 Hz), 7.32 (t, 2H, J=7.4 Hz),7.22 (t, 1H, J=7.2 Hz), 5.97 (d, 1H, J=5.2 Hz), 5.63 (br, 1H), 5.45 (br,2H), 4.98 (br, 1H), 4.24 (m, 4H), 4.64 (br, 1H), 3.79 (td, 2H, J=10.5Hz, J=15.6 Hz).

Example 11((2R,3S,4R,5R)-5-{6-[(1,3-Benzodioxol-5-ylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl-sulfamate(I-63)

The title compound was prepared as described in Example 6, step c, using3,4-methylenedioxybenzylamine

LCMS: R.t. 1.32 min, ES+ 481 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.35 (s, 1H), 8.25 (s, 1H), 7.62 (s, 2H),6.95 (s, 1H), 6.85 (d, 2H, J=0.5 Hz), 5.98 (m, 3H), 5.64 (d, 1H, J=5.9Hz), 5.46 (d, 1H, J=5.3 Hz), 4.66 (dd, 2H, J=5.3 Hz, J=10.7 Hz), 4.25(m, 4H).

Example 12((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-methoxyethyl)amino]-9H-purin-9-yl}-tetrahydrofuran2-yl)methyl-sulfamate(I-21)

The title compound was prepared as described in Example 6, step c, usingO-methyl ethanolamine.

LCMS: R.t. 0.95 min, ES+ 405 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.39 (br, 2H), 6.20 (d, 1H, J=5.0 Hz), 4.78(t, 1H, J=5.1 Hz), 4.48 (m, 4H), 3.91 (br, 2H), 3.77 (t, 1H, J=5.4 Hz),3.52 (m, 3H).

Example 13((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-pyrrolidin-1-ylethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl-sulfamate(I-64)

The title compound was prepared as described in Example 6, step c, usingN-ethylamino-tetrahydropyrrole and isolated as the formate salt.

LCMS: R.t. 0.92 min, ES+ 444 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.41 (s, 1H), 8.34 (s, 1H), 7.64 (s, 2H),6.00 (d, 1H, J=5.3 Hz), 4.67 (t, 1H, J=5.2 Hz), 4.25 (m, 4H), 3.86 (br,2H), 3.68 (br, 2H), 3.45 (d, 2H, J=4.9 Hz), 3.10 (br, 2H), 1.95 (br,4H).

Example 14((2R,3S,4R,5R)-5-{6-[(4-Fluorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl-sulfamate(I-65)

The title compound was prepared as described in Example 6, step c, using4-fluorobenzylamine.

LCMS: R.t. 1.38 min, ES+ 455 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.35 (s, 1H), 8.25 (s, 1H), 7.61 (s, 2H),7.40 (dd, 2H, J=5.7 Hz, J=8.5 Hz), 7.13 (t, 2H, J=8.9 Hz), 5.97 (d, 1H,J=5.3 Hz), 5.64 (d, 1H, J=5.9 Hz), 5.46 (d, 1H, J=5.3 Hz), 4.68 (m, 2H),4.24 (m, 4H).

Example 15((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl-sulfamate(I-25)

The title compound was prepared as described in Example 6, step c, usingN-ethylamino-morpholine

LCMS: R.t. 1.05 min, ES+ 460 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.41 (s, 1H), 8.34 (s, 1H), 7.64 (s, 2H),6.00 (d, 1H, J=5.3 Hz), 4.26 (m, 4H), 5.57 (br, 2H), 4.67 (t, 1H, J=5.2Hz), 3.88 (br, 8H), 3.42 (br, 4H).

Example 16((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl-sulfamate(I-4)

The title compound was prepared as described in Example 6, step c, using1-methylamino naphthalene.

LCMS: R.t. 1.42 min, ES+ 487 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.46 (s, 1H), 8.33 (s, 1H), 8.23 (s, 2H),7.94 (dd, 1H, J=2.7 Hz, J=6.7 Hz), 7.81 (dd, 1H, J=1.8 Hz, J=7.3 Hz),7.57 (m, 4H), 7.43 (t, 1H, J=6.3 Hz), 5.95 (d, 1H, J=5.3 Hz), 5.61 (d,1H, J=5.9 Hz), 5.44 (d, 1H, J=5.3 Hz), 5.18 (br, 2H), 4.64 (dd, 1H,J=5.0 Hz, J=10.3 Hz), 4.21 (m, 4H).

Example 17((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(piperidin-4-ylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl-sulfamate(I-26)

The title compound was prepared as described in Example 6, step c, using4-methylamino piperidine and isolated as the formate salt

LCMS: R.t. 1.88 min, ES+ 444 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.35 (s, 1H), 8.27 (s, 1H), 7.64 (s, 2H),5.98 (d, 1H, J=5.3 Hz), 4.66 (t, 1H, J=5.1 Hz), 4.25 (m, 4H), 3.36 (m,4H), 2.86 (dd, 2H, J=11.6 Hz, J=23.0 Hz), 1.99 (br, 1H), 1.85 (d, 1H,J=14.5 Hz), 1.37 (dd, 2H, J=13.1 Hz, J=24.6 Hz).

Example 18((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-methoxybenzyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methylsulfamate (I-27)

The title compound was prepared as described in Example 6, step c, using2-methoxybenzylamine.

LCMS: R.t. 1.35 min, ES+ 467 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.37 (s, 1H), 8.22 (s, 1H), 7.62 (s, 2H),7.24 (t, 1H, J=7.7 Hz), 7.13 (d, 1H, J=7.4 Hz), 7.01 (d, 1H, J=8.1 Hz),6.87 (t, 1H, J=7.4 Hz), 5.98 (d, 1H, J=5.3 Hz), 5.65 (d, 1H, J=5.9 Hz),5.47 (d, 1H, J=5.3 Hz), 4.69 (br, 2H), 4.26 (m, 4H), 3.87 (s, 3H).

Example 19[(2R,3S,4R,5R)-5-(6-{[2-(4-Benzylpiperazin-1-yl)ethyl]amino}-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl-sulfamate(I-28)

The title compound was prepared as described in Example 6, step c, using1-N-ethylamino(4-N-benzyl)piperazine, and isolated as the formate salt.

LCMS: R.t. 0.94 min, ES+ 549 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.30 (s, 1H), 7.97 (s, 1H), 7.64 (s, 2H),7.45 (m, 5H), 5.99 (d, 1H, J=5.3 Hz), 5.59 (br, 2H), 4.66 (t, 1H, J=5.1Hz), 4.25 (m, 4H), 3.82 (br, 4H), 3.09 (br, 10H).

Example 20[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-[{4-(trifluoromethoxy)benzyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl-sulfamate(I-30)

The title compound was prepared as described in Example 6, step c, using4-trifluoromethoxybenzylamine.

LCMS: R.t. 1.49 min, ES+ 521 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): S 8.38 (s, 1H), 8.27 (s, 1H), 7.63 (s, 2H),7.49 (d, 2H, J=8.6 Hz), 7.33 (d, 2H, J=8.0 Hz), 5.99 (d, 1H, J=5.3 Hz),5.65 (d, 1H, J=5.9 Hz), 5.48 (d, 1H, J=5.4 Hz), 4.77 (br, 2H), 4.67 (dd,1H, J=5.5 Hz, J=10.9 Hz), 4.26 (m, 4H).

Example 21{(2R,3S,4R,5R)-5-[6-(Benzylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methylsulfamate (I-6)

The title compound was prepared as described in Example 6, step c, usingbenzylamine.

LCMS: R.t. 1.16 min, ES+ 437 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.25 (m, 2H) ppm 7.30 (m, 5H) ppm 6.06 (d,1H, J=4.9 Hz) ppm 4.64 (dd, 1H, J=4.3 Hz, J=9.1 Hz) ppm 4.36 (m, 4H)

Example 22N-[((2R,3S,4R,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-15) Step a: tert-Butyl (aminosulfonyl) carbamate

A solution of tert-butyl alcohol (5.930 g, 0.080 mol) in ethyl acetate(100 mL) was cooled in an acetonitrile/dry ice bath under nitrogen andchlorosulfonyl isocyanate (6.964 mL, 0.080 mol) was added dropwise. Theclear solution was stirred at about −40° C. under nitrogen for 2 h. Thecooling bath was changed for a chloroform/dry ice bath, the reactionflask was topped with a cold finger containing acetone/dry ice, andammonia was condensed in the reaction for 20 min to lead to the rapidformation of a white solid. The reaction was stirred at about −60° C.for 3 h. The cold finger and the cooling bath were removed and thereaction allowed to warm to room temperature under a stream of nitrogen.Water (100 mL) was added. The phases were separated and the aqueouswashed once with EtOAc (50 mL). The aqueous was cooled in ice/water bathand acidified to pH˜2 by adding 20% aq H₂SO₄ dropwise to obtain a whiteprecipitate, which was isolated by filtration and washed with water. Theproduct was dried overnight in vacuum oven at 40° C. and obtained as awhite solid (9.440 g, 60%).

LCMS: R.t. 1.07 min ES− 195 (formic acid).

Step b: tert-Butyl(aminosulfonyl){[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]-dioxol-4-yl]methyl}carbamate

(2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(6.352 g, 0.01944 mol), N-Boc-sulfamide (5.717 g, 0.02913 mol) andtriphenylphosphine (6.119 g, 0.02333 mol) were dissolved in ethylacetate (200 mL) under nitrogen and diisopropyl azodicarboxylate (5.742mL, 0.02916 mol) was added dropwise. The solution was stirred for 2 h,and then concentrated in vacuo. The residue was purified by flashchromatography (Hex/EtPOAc 25% to 65%) to afford 5.460 g of product as awhite solid and 1.40 g of product with triphenylphosphine oxideimpurity. This second batch was purified by flash chromatography(Hex/EtOAc 20% to 60%). The product was obtained as a white solid (6.160g, 63%).

LCMS: R.t. 1.66 min ES+ 505 (formic acid).

Step c:N-[((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl)methyl]sulfamide

tert-Butyl(aminosulfonyl){[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}carbamate(6.160 g, 0.01220 mol) was treated with trifluoroacetic acid/methylenechloride 1:2 (60 mL) for 30 min. Toluene was added and the solution wasconcentrated to dryness to obtain a white solid which was purified byflash chromatography (MeOH/DCM 1% to 6%). The product was obtained as awhite solid (4.939 g, 83%).

LCMS: R.t. 1.18 min ES+ 405 (formic acid

Step d:N-[((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl]sulfamide

N-[((3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl)methyl]sulfamide(4.100 g, 0.01013 mol), (S)-(+)-1-aminoindane (1.624 mL, 0.01266 mol)and triethylamine (3.529 mL, 0.02532 mol) were refluxed in ethanol (100mL) overnight. The reaction mixture was concentrated in vacuo, and theresidue was purified by flash chromatography DCM/EtOAc 25% to 60%). Theproduct was obtained as a white solid (4.185 g, 82%).

LCMS: R.t. 1.56 min ES+ 502 (formic acid).

Step e:N-[((2R,3S,4R,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-15)

N-[((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl]sulfamide(4.185 g, 0.008344 mol) was treated with trifluoroacetic acid/water 9:1(50 mL) at room temperature for 15 min. The pinkish solution wasconcentrated in vacuo and the residue precipitated from methanol/ether.The product was obtained as an off-white solid (3.434 g, 89%).

LCMS: R.t. 1.31 min ES+ 463 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO+D₂O): δ 8.40 (br s, 1H), 8.33 (s, 1H),7.29-7.11 (m, 4H), 5.86 (m, 1H), 5.17 (m, 1H), 4.68 (m, 1H), 4.13 (m,2H), 3.18 (m, 2H), 3.02 (m, 1H), 2.85 (m, 1H), 2.09 (m, 1H).

Example 23N-{[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide(I-13)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using (1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylamine, and purified by preparative HPLC.

LCMS: R.t. 0.98 min ES+ 478 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO+D₂O): δ 8.33 (s, 1H), 8.30 (br s, 1H),7.28-7.13 (m, 4H), 5.85 (d, 1H, J=7.0 Hz), 5.68 (br s, 1H), 4.72 (dd,1H, J=6.9 Hz, J=4.9 Hz), 4.57 (m, 1H), 4.14 (m, 2H), 3.26-3.10 (m, 3H),2.88 (d, 1H, J=15.5 Hz).

Example 24N-[((2R,3S,4R,5R)-5-{6-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-46)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using (R)-(−)-1-aminoindane, and purified bypreparative HPLC.

LCMS: R.t. 1.25 min ES+ 462.5 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.34 (s, 1H), 8.28 (s, 1H), 8.21 (m, 1H),7.61 (m, 1H), 7.28-7.09 (m, 4H), 6.62 (s, 2H), 5.95 (m, 1H), 5.86 (d,1H, J=6.9 Hz), 5.46 (m, 1H), 5.27 (m, 1H), 4.77 (m, 1H), 4.17-4.11 (m,2H), 3.27-3.10 (m, 2H), 3.03 (m, 1H), 2.84 (m, 1H), 2.16 (m, 1H).

Example 25N-{[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1-methyl-1H-pyrazol-4-yl)methyl]-amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide(I-38)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 1-methyl-1H-pyrazol-4-yl methylamine, andpurified by preparative HPLC.

LCMS: R.t. 0.74 min ES+ 440 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.33 (s, 1H), 8.26 (m, 2H), 8.02 (d, 1H,J=7.0 Hz), 7.57 (m, 2H), 7.35 (s, 1H), 6.60 (s, 2H), 5.84 (d, 1H, J=6.9Hz), 5.44 (d, 1H, J=6.4 Hz), 4.74 (dd, 1H, J=6.6 Hz, J=5.4 Hz), 4.51 (m,2H), 4.16-4.06 (m, 2H), 3.75 (s, 3H), 3.26-3.10 (m, 2H).

Example 26N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-43)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 1-naphthylmethyl amine, and purified bypreparative HPLC.

LCMS: R.t. 1.28 min ES+ 486 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.53 (m, 1H), 8.36 (s, 1H), 8.26 (m, 1H),8.22 (s, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.56 (m, 3H), 7.45 (m, 2H),6.60 (s, 2H), 5.85 (d, 1H, J=6.6 Hz), 5.45 (d, 1H, J=6.0 Hz), 5.26 (m,1H), 5.19 (m, 1H), 4.75 (dd, 1H, J=11.3 Hz, J=5.6 Hz), 4.31 (m, 1H),4.16-4.10 (m, 2H), 3.26-3.09 (m, 2H).

Example 27N-[((2R,3S,4R,5R)-5-{6-[(2,2-Diphenylethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-42)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using α-phenylbenzylamine, and purified bypreparative HPLC.

LCMS: R.t. 1.39 min ES+ 526 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): S 8.29 (s, 1H), 8.27 (m, 1H), 7.90 (m, 1H),7.53 (m, 1H), 7.34-7.26 (m, 8H), 7.20-7.15 (m, 2H), 6.60 (s, 2H), 5.81(d, 1H, J=6.9 Hz), 4.72 (m, 1H), 4.60 (m, 1H), 4.14-4.10 (m, 4H),3.25-3.08 (m, 2H).

Example 28N-[((2R,3S,4R,5R)-5-{6-[(1-Benzothien-3-ylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-44)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 1-benzothien-3-ylmethylamine, and purified bypreparative HPLC.

LCMS: R.t. 1.27 min ES+ 492 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.51 (m, 1H), 8.35 (s, 1H), 8.26 (s, 1H),8.02 (d, 1H, J=7.0 Hz), 7.97 (m, 1H), 7.55 (dd, 1H, J=8.2 Hz, J=4.5 Hz),7.52 (s, 1H), 7.39 (m, 2H), 6.60 (s, 2H), 5.84 (d, 1H, J=7.0 Hz), 5.44(d, 1H, J=6.4 Hz), 5.26 (d, 1H, J=4.3 Hz), 4.75 (dd, 1H, J=11.6 Hz,J=6.4 Hz), 4.16-4.06 (m, 4H), 3.23-3.09 (m, 2H).

Example 29N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(3-methoxybenzyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-33)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 3-methoxybenzylamine, and purified bypreparative HPLC.

LCMS: R.t. 1.08 min ES+ 466 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.45 (br s, 1H), 8.35 (s, 1H), 8.21 (s,1H), 7.55 (m, 1H), 7.20 (m, 1H), 6.90 (m, 2H), 6.78 (m, 1H), 6.59 (s,2H), 5.84 (d, 1H, J=6.9 Hz), 5.44 (m, 1H), 5.25 (m, 1H), 4.75 (m, 1H),4.18-4.05 (m, 4H), 3.70 (s, 3H), 3.26-3.08 (m, 2H).

Example 30N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-thienylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-37)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 2-thienylmethylamine, and purified bypreparative HPLC.

LCMS: R.t. 1.03 min ES+ 442 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.54 (br s, 1H), 8.36 (s, 1H), 8.27 (br s,1H), 7.54 (m, 1H), 7.33 (dd, 1H, J=5.1 Hz, J=1.3 Hz), 7.03 (dd, 1H,J=3.5 Hz, J=1.1 Hz), 6.93 (dd, 1H, J=5.1 Hz, J=3.4 Hz), 6.61 (s, 2H),5.85 (d, 1H, J=7.0 Hz), 4.86 (m, 2H), 4.75 (dd, 1H, J=6.8 Hz, J=5.2 Hz),4.16-4.10 (m, 2H), 3.26-3.10 (m, 2H).

Example 31N-{[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(2R)-2-hydroxy-2-(3-hydroxyphenyl)-ethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide(I-68)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using (2R)-2-hydroxy-2-(3-hydroxyphenyl)ethylamine,and purified by preparative HPLC.

LCMS: R.t. 0.81 min ES+ 482 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): S 8.33 (s, 1H), 8.25 (s, 1H), 7.63 (m, 1H),7.56 (m, 1H), 7.11 (t, 1H, J=7.8 Hz), 6.83 (m, 2H), 6.63 (m, 1H), 6.60(s, 2H), 5.84 (d, 1H, J=6.8 Hz) 5.49 (m, 1H), 5.45 (d, 1H, J=6.4 Hz),5.25 (d, 1H, J=3.7 Hz), 4.76 (m, 2H), 4.15-4.06 (m, 2H), 3.71 (m, 1H),3.53 (m, 1H), 3.26-3.10 (m, 2H).

Example 32N-[((2R,3S,4R,5R)-5-{6-[(1,3-Benzodioxol-5-ylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-39)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 1-(1,3-benzodioxol-5-yl)methanamine, andpurified by preparative HPLC.

LCMS: R.t. 1.06 min ES+ 480 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.43 (m, 1H), 8.35 (s, 1H), 8.22 (s, 1H),7.55 (m, 1H), 6.92 (s, 1H), 6.78 (m, 1H), 6.82 (m, 2H) 6.60 (s, 2H),5.95 (s, 2H), 5.84 (d, 1H, J=6.7 Hz), 4.74 (dd, 1H, J=6.5 Hz, J=6.5 Hz),4.60 (m, 2H), 4.16-4.10 (m, 2H), 3.26-3.10 (m, 21-1).

Example 33N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-methoxyethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-35)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 2-methoxyethylamine, and purified bypreparative HPLC.

LCMS: R.t. 0.68 min ES+ 404 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.34 (s, 1H), 8.23 (s, 1H), 7.85 (m, 1H),7.54 (m, 1H), 6.60 (s, 2H), 5.84 (d, 1H, J=7.0 Hz), 4.73 (dd, 1H, J=6.7Hz, J=5.2 Hz), 4.16-4.10 (m, 2H), 3.65 (m, 2H), 3.52 (t, 2H, J=5.7 Hz),3.26 (s, 3H), 3.25-3.10 (m, 2H).

Example 34N-{[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1R)-2-hydroxy-1-phenylethyl]-amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide(I-45)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using (1R)-2-hydroxy-1-phenylethyl]amino, andpurified by preparative HPLC.

LCMS: R.t. 0.94 min ES+ 466 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.36 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H,J=8.5 Hz), 7.53 (m, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 6.59(s, 2H), 5.83 (d, 1H, J=6.7 Hz) 5.42 (m, 2H), 5.25 (m, 1H), 4.95 (m,1H), 4.72 (m, 1H), 4.15-4.09 (m, 2H), 3.84-3.68 (m, 2H), 3.26-3.10 (m,21-1).

Example 35N-{[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(5-methylpyrazin-2-yl)methyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide(I-36)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 5-methylpyrazin-2-yl-methylamine, and purifiedby preparative HPLC.

LCMS: R.t. 0.79 min ES+ 452 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.50 (m, 1H), 8.45 (m, 2H), 8.38 (s, 1H),8.20 (s, 1H), 7.50 (m, 1H), 6.59 (s, 2H), 5.85 (d, 1H, J=6.9 Hz), 4.80(m, 2H), 4.74 (dd, 1H, J=6.6 Hz, J=5.4 Hz), 4.16-4.09 (m, 2H), 3.26-3.10(m, 2H), 2.45 (s, 3H).

Example 36N-({(2R,3S,4R,5R)-5-[6-(Benzylamino)-9H-purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl}methyl)sulfamide(I-19)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using benzylamine, and purified by preparative HPLC.

LCMS: R.t. 1.02 min ES+ 436 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.48 (m, 1H), 8.35 (s, 1H), 8.21 (s, 1H),7.56 (dd, 1H, J=7.8 Hz, J=3.7 Hz), 7.36-7.18 (m, 5H), 6.60 (s, 2H), 5.85(d, 1H, J=6.7 Hz), 5.45 (d, 1H, J=6.4 Hz), 5.26 (m, 1H), 4.74 (m, 3H),4.14 (m, 2H), 3.27-3.09 (m, 2H).

Example 37N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-phenoxyethyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-34)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using 2-phenoxyethylamine, and purified bypreparative HPLC.

LCMS: R.t. 1.11 min ES+ 466 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.35 (s, 1H), 8.26 (br s, 1H), 8.04 (br s,1H), 7.53 (m, 1H), 7.27 (dd, 2H, J=8.9 Hz, J=7.1 Hz), 6.93 (m, 3H), 6.60(s, 2H), 5.85 (d, 1H, J=6.8 Hz), 5.44 (d, 1H, J=6.4 Hz), 5.25 (d, 1H,J=4.3 Hz), 4.74 (dd, 1H, J=11.7 Hz, J=6.4 Hz), 4.19-4.09 (m, 4H), 3.87(m, 2H), 3.27-3.09 (m, 2H).

Example 38N-{[2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1S)-2-hydroxy-1-phenylethyl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl}sulfamide(I-20)

The title compound was prepared as described in Example 22, step d, andexample 22, step e, using (S)-2-amino-2-phenylethanol, and purified bypreparative HPLC.

LCMS: R.t. 0.90 min ES+ 466 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.36 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H,J=8.5 Hz), 7.53 (m, 1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 6.59(s, 2H), 5.83 (d, 1H, J=6.7 Hz) 5.42 (m, 2H), 5.25 (m, 1H), 4.95 (m,1H), 4.72 (m, 1H), 4.15-4.09 (m, 2H), 3.84-3.68 (m, 2H), 3.26-3.10 (m,2H).

Example 39((2R,3S,4R,5R)-5-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-9) Step a:[(3aR,4R,6R,6aR)-6-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-methanol

To a suspension of(2R,3R,4S,5R)-2-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol(0.5 g, 1.75 mmol) and 2,2-dimethoxypropane (1.12 mL, 8.75 mmol) inacetone (40 mL) was added 333 mg (1.75 mmol) p-TsOH monohydrate. Theresulting clear solution was stirred for 13 hours and then saturated aqNaHCO₃ was added. Approximately half the solvent was removed in vacuoand the resulting suspension was diluted with water and extracted withCH₂Cl₂ (4×). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product wasused without further purification.

LCMS: R.t. 1.49 min, ES+ 326 (formic acid).

Step b{(3aR,4R,6R,6aR)-6-[4-((S)-Indan-1-ylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl}-methanol

A solution of[(3aR,4R,6R,6aR)-6-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol(574 mg, 1.76 mmol), diisopropylethylamine (1.2 mL, 7.04 mmol) and(S)-(+)-1-aminoindane (680 μL, 5.27 mmol) in n-butanol 3.3 mL) wasdivided into two portions and each portion was microwave irradiated at190° C. for 900 s. The solvent was removed in vacuo and the combinedcrude portions were purified by silica gel chromatography (0 to 5%MeOH/CH₂Cl₂) to afford 460 mg (62% over two steps) of the titlecompound.

LCMS: R.t. 1.31 min, ES+ 423 (formic acid).

Step c: Sulfamic acid(3aR,4R,6R,6aR)-6-[4-((S)-indan-1-ylamino)-pyrrolo[2,3-d]-pyrimidin-7-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylester

To a solution of the alcohol formed in Example 39, step b (349 mg, 0.83mmol), and triethylamine (231 μL, 1.66 mmol) in DMF (14 mL) was addeddropwise 620 μL of a 2M solution of the chlorosulfonamide inacetonitrile and the cloudy solution was stirred for 50 minutes. Thereaction was diluted with EtOAc and water/brine, the layers wereseparated, and the aqueous layer was extracted with EtOAc (1×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude material was purified bysilica gel chromatography (0 to 5% MeOH/CH₂Cl₂) to afford 233 mg (56%)of the title compound.

LCMS: R.t. 1.48 min, ES+ 502 (formic acid).

Step d:((2R,3S,4R,5R)-5-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-9)

The isopropylidene protected diol described in Example 39, step c (100mg) was dissolved in approximately 3 mL of 10% water in TFA. After 18minutes the solvent was removed in vacuo and the crude product waspurified by HPLC to obtain 26 mg (28%) of product.

LCMS: R.t. 1.08 min, ES+ 462 (formic acid).

¹H-NMR (400 MHz, CD₃OD): 5 (s, 1H); 7.39 (d, J=3.8 Hz, 1H); 7.33-7.20(m, 4 H); 6.76 (d, J=3.7 Hz, 1H); 6.31 (d, J=5.6 Hz, 1H); 5.92 (t, J=7.7Hz, 1H); 5.55 (s, 1H); 4.51 (t, J=5.4 Hz, 1H); 4.44-4.31 (m, 3H);3.16-3.09 (m, 1H); 3.03-2.95 (m, 1H); 2.74-2.66 (m, 1H); 2.13-2.04 (m,1H).

Example 40((2R,3S,4R,5R)-5-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-1) Step a:(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-tetrahydrofuran-3-ol

To a solution of(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol(3.78 g, 15.04 mmol) and imidazole (2.46 g, 36.10 mmol) in DMF (20 mL)was added tert-butyldimethylsilylchloride (2.38 g, 15.80 mmol) and thesolution was stirred at room temperature for approximately 4 hours. Thereaction mixture was diluted with water, and extracted three times withEtOAc. The combined organics were dried over Na₂SO₄ and concentrated invacuo. The product was isolated as a white solid (4.138 g, 75%) and wasused without further purification.

LCMS: R.t. 1.31 min, ES+ 366 (formic acid).

Step b:(2R,3S,5R)-5-(6-Amino-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-tetrahydrofuran-3-ylacetate

A solution of(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-ol(4.138 g, 11.32 mmol) and catalytic amount of DMAP in pyridine wascooled with an ice bath. Acetic anhydride (1.124 mL, 11.89 mmol) wasadded slowly and the reaction mixture was stirred while warming to roomtemperature for approximately 5 hours. The reaction was quenched with 1NHCl solution and extracted three times with EtOAc. The combined organicphases were washed with aqueous CuSO₄ solution and dried over Na₂SO₄. Awhite solid was isolated upon removing the solvent (4.143 g, 90%) andthe crude material was used without further purification.

LCMS: R.t. 1.61 min, ES+ 409 (formic acid).

Step c:(2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-tetrahydrofuran-3-ylacetate

To a solution of(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl-(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-ylacetate (2.00 g, 4.91 mmol) in dibromomethane (98.2 mL) were addedtrimethylsilylbromide (0.717 mL, 5.55 mmol) then t-butylnitrite (3.98mL, 33.44 mmol). The reaction mixture was stirred at room temperaturefor approximately 3 hours before being slowly poured into a 1:1 mixtureof saturated NaHCO₃: CH₂Cl₂. The organics were washed with water thenbrine. After drying over Na₂SO₄, the solvent was removed in vacuo. Thecrude product was purified by flash chromatography (0% to 30% EtOAc/Hex)to obtain the title compound as a yellow oil (1.26 g, 55%).

LCMS: R.t. 2.16 min, ES+ 473 (formic acid).

Step d(2R,3S,5R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-ylacetate

A solution of(2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)-silyl]oxy}methyl)tetrahydrofuran-3-ylacetate (359 mg, 0.76 mmol), diisopropylethylamine (265 μL, 1.52 mmol)and (S)-(+)-1-aminoindane (146 μL, 1.14 mmol) in ethanol (13 mL) washeated to reflux for 17 h. The solvent was removed in vacuo and theresidue purified by silica gel chromatography (10 to 50% EtOAc/hexanes)to afford 322 mg (81%) of product.

LCMS: R.t. 2.31 min, ES+ 525 (formic acid).

Step e:(2R,3S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-(hydroxymethyl)tetrahydrofuran-3-ylacetate

To a solution of(2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-ylacetate (440 mg, 0.84 mmol) in pyridine/tetrahydrofuran (1:1, 3.4 mL)was added approximately 20 drops of hydrofluoric acid in pyridine (2.0M). After stirring for 17 h, the reaction was quenched with saturatedaqueous NaHCO₃ and extracted with dichloromethane. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification via flash chromatography (40 to 100%EtOAc/hexanes) afforded 314 mg (91%) of the title compound.

LCMS: R.t. 1.39 min, ES+ 410 (formic acid).

Step f:(2R,3S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-ylacetate

(2R,3S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-(hydroxymethyl)tetrahydrofuran-3-ylacetate (199 mg, 0.29 mmol) was treated with chlorosulfonamide asdescribed in Example 39, step c. The product was purified by flashchromatography (0 to 5% MeOH/CH₂Cl₂) to afford 105 mg (74%) of the titlecompound.

LCMS: R.t. 1.52 min, ES+ 489 (formic acid).

Step g:((2R,3S,4R,5R)-5-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-1)

(2R,3S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-ylacetate (96 mg, 0.20 mmol) was dissolved in 2.6 mL of 7M NH₃/MeOH andstirred for one hour. Approximately 1 mL tetrahydrofuran was added, andthe resulting solution was stirred for 3 hours. The solvent was removedin vacuo and the residue purified by silica gel chromatography (0% to10% MeOH/CH₂Cl₂) to afford 59 mg (66%) of the title compound.

LCMS: R.t. 1.30 min, ES+ 447 (formic acid).

¹H NMR (400 MHz, CD₃OD): δ 8.31 (s, 1H); 8.25 (s, 1H); 7.29-7.13 (m,4H); 6.49 (t, J=6.8 Hz, 1H); 5.87 (bs, 1H); 4.64-4.61 (m, 1H); 4.39-4.29(m, 2H); 4.25-4.21 (m, 1H); 3.32-3.31 (m, 1H); 3.12-3.03 (m, 1H);2.98-2.87 (m, 1H); 2.85-2.76 (m, 1H); 2.72-2.62 (m, 1H); 2.54-2.46 (m,1H); 2.08-1.95 (m, 1H).

Example 41((2R,3S,4R,5R)-5-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-53) Step a:(2R,3R,5S)-2-(6-Chloro-purin-9-yl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-furan-3-ylacetate

To a solution of(2R,3R,5S)-2-(6-amino-purin-9-yl)-5-(tert-butyl-dimethyl-silanyloxymethyl)tetrahydrofuran-3-ol(727 mg, 1.99 mmol) (Norbeck, D. W.; Kramer, J. B. J. Am. Chem. Soc.1988, 110, 7217-7218) in pyridine (10 mL) at 0° C. was added dropwiseacetic anhydride (207 μL, 2.19 mmol). After stirring for two hours, thesolution was warmed to room temperature and a few crystals of DMAP wereadded. After one hour, the reaction was quenched with saturated aqueousNaHCO₃ and poured into water/1 N HCl/EtOAc. The layers were separatedand the aqueous layer was extracted with EtOAc (2×). The combinedorganics were washed once with brine, dried over Na₂SO₄, filtered, andthe solvent removed in vacuo. The crude product was purified by silicagel chromatography (20 to 70% EtOAc/hexanes) to afford 610 mg (75%) ofthe acylated compound.

LCMS: R.t. 1.66 min, ES+ 408 (formic acid).

Of this material, 394 mg (0.97 mmol) was dissolved in CH₂Cl₂ (29 mL) andcooled to 0° C. To this was added trimethylsilylchloride (1.1 mL, 8.73mmol) dropwise, followed by a solution of tert-butylnitrite (692 μL,5.82 mmol) in CH₂Cl₂ (10 mL). After stirring for 30 minutes the solutionwas warmed to room temperature. After stirring for one hour, thesolution was quenched with saturated aqueous NaHCO₃ and extracted withEtOAc. The combined organics were washed once with brine, dried overNa₂SO₄, filtered, and the solvent removed in vacuo. The crude productwas purified by silica gel chromatography (5 to 30% EtOAc/hexanes) toafford 136 mg (33%) of the title compound.

LCMS: R.t. 2.23 min, ES+ 427 (formic acid standard).

Step b:(2R,3R,5S)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[6-((S)-indan-1-ylamino)-purin-9-yl]tetrahydro-furan-3-ylacetate

A solution of(2R,3R,5S)-2-(6-chloro-purin-9-yl)-5-(tert-butyldimethylsilanyloxymethyl)tetrahydrofuran-3-ylacetate (167 mg, 0.39 mmol), diisopropylethylamine (109 μL, 0.78 mmol)and (S)-(+)-1-aminoindane (75 μL, 0.59 mmol) in ethanol (6.3 mL) washeated to reflux for 15 hours. The solvent was removed in vacuo and theresidue purified by silica gel chromatography (0 to 5% MeOH/CH₂Cl₂) toafford 109 mg (53%) of product.

LCMS: R.t. 2.43 min, ES+ 524 (formic acid).

Step c:(2R,3R,5S)-5-Hydroxymethyl-2-[6-((S)-indan-1-ylamino)-purin-9-yl]tetrahydro-furan-3-ylacetate

To a solution of(2R,3R,5S)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-[6-((S)-indan-1-ylamino)purin-9-yl]tetrahydrofuran-3-ylacetate (109 mg, 0.20 mmol) in pyridine/tetrahydrofuran (1:1, 2 mL) wasadded approximately 6 drops of hydrofluoric acid in pyridine (2.0 M).After stirring for 5 h the reaction was quenched with saturated aqueousNaHCO₃ and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo toafford a quantitative amount of the crude product.

LCMS: R.t. 1.45 min, ES+ 410 (formic acid).

Step d:(2R,3R,5S)-2-[6-((S)-Indan-1-ylamino)-purin-9-yl]-5-sulfamoyloxymethyl-tetrahydrofuran-3-ylacetate

To a solution of(2R,3R,5S)-5-hydroxymethyl-2-[6-((S)-indan-1-ylamino)-purin-9-yl]tetrahydrofuran-3-ylacetate (0.20 mmol) and triethylamine (56 μL, 0.0.40 mmol) in DMF (3.3mL) was added dropwise 150 μL of a 2M solution of the chlorosulfonamidein acetonitrile and the cloudy solution was stirred. Identical amountsof triethylamine and the chlorosulfonamide solution were added after 2.5and 4 hours. The reaction was diluted with EtOAc and water, the layerswere separated, and the aqueous layer was extracted with EtOAc (1×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude material was purified bysilica gel chromatography (0% to 10% MeOH/CH₂Cl₂) to afford 51 mg (52%)of the title compound.

LCMS: R.t. 1.52 min, ES+ 489 (formic acid).

Step e:((2R,3S,4R,5R)-5-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-53)

(2R,3R,5S)-2-[6-((S)-Indan-1-ylamino)-purin-9-yl]-5-sulfamoyloxymethyl-tetrahydrofuran-3-ylacetate (50 mg, 0.10 mmol) was dissolved in 1.3 mL of 7M NH₃/MeOH andstirred for one hour. Approximately 1 mL methanol was added, and theresulting solution was stirred for 1.5 hours. The solvent was removed invacuo and the residue purified by silica gel chromatography (0 to 10%MeOH/CH₂Cl₂) to afford 34 mg (76%) of product.

LCMS: R.t. 1.33 min, ES+ 447 (formic acid).

¹H NMR (400 MHz, CD₃OD): δ 8.38 (bs, 1H); 8.31 (s, 1H); 7.35-7.20 (m,4H); 6.11 (m, 1H); 5.95 (bs, 1H); 4.81-4.78 (m, 2H); 4.52-4.49 (m, 1H);4.36 (dd, J=4.2, 11.1 Hz, 1H); 3.41 (s, 2H); 3.18-3.11 (m, 1H);3.04-2.96 (m, 1H); 2.77-2.69 (m, 1H); 2.47-2.40 (m, 1H); 2.23-2.18 (m,1H); 2.13-2.04 (m, 1H).

Example 42((2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methylsulfamate (I-61) Step a:6-chloro-9-[(6aR,8R,9S,9aR)-2,2,4,4-Tetraisopropyl-9-methoxytetrahydro-6H-furo-[3,2-f][1,3,5,2,4]-trioxadisilocin-8-yl]-9H-purine

To a suspension of(6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol(300 mg, 0.57 mmol) and Cs₂CO₃ (1.86 g, 5.7 mmol) in DMF (5.7 mL) at 0°C. was added MeI (350 μL, 5.7 mmol) dropwise. The suspension was stirredfor 3 hours, quenched with saturated aqueous NH₄Cl and CH₂Cl₂. Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified by silica gelchromatography (0 to 20% EtOAc/hexanes) to afford 221 mg (71%) of thetitle compound.

LCMS: R.t. 3.12 min, ES+ 543 (formic acid standard).

Step b:N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purin-6-amine

A solution of6-chloro-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-j][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine(221 mg, 0.41 mmol), diisopropylethylamine (114 μL, 0.82 mmol) and(S)-(+)-1-aminoindane (78 μL, 0.61 mmol) in ethanol (7 mL) was heated toreflux for 24 hours. The solvent was removed in vacuo and the residuepurified by silica gel chromatography (10 to 30% EtOAc/hexanes) toafford 239 mg (91%) of the title compound.

LCMS: R.t. 3.20 min, ES+ 641 (formic acid standard).

Step c:3-{[(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-yl]oxy}-1,1,3,3-tetraisopropyl-disiloxan-1-ol

To a solution ofN-[(1S)-2,3-dihydro-1H-inden-1-yl]-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purin-6-amine(238 mg, 0.37 mmol) in methanol/dioxane (1:4, 8 mL) was added 3.2 mL0.2N HCl. After stirring for two hours the solvent was removed in vacuoand the residue purified by silica gel chromatography (10 to 50%EtOAc/hexanes) to afford 32 mg (13%) of the title compound.

LCMS: R.t. 2.31 min, ES+ 659 (formic acid standard).

Step d:{(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-[(3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl)oxy]-4-methoxytetrahydrofuran-2-yl}-methylsulfamate

3-{[(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-yl]oxy}-1,1,3,3-tetraisopropyldisiloxan-1-olwas reacted with chlorosulfonamide as described in Example 41, step d.The crude product was reacted directly.

LCMS: R.t. 2.62 min, ES+ 737 (formic acid standard).

Step e:((2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methylsulfamate (I-61)

{(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-[(3-hydroxy-1,1,3,3-tetraisopropyldisiloxanyl)oxy]-4-methoxytetrahydrofuran-2-yl}methylsulfamate was reacted with hydrofluoric acid in pyridine (2.0 M)essentially as described in Example 41, step c. The product was purifiedby flash chromatography (0 to 10% MeOH/CH₂Cl₂) affording 17 mg (74%)

LCMS: R.t. 1.35 min, ES+ 477 (formic acid standard).

¹H NMR (400 MHz, CD₃OD): δ 8.38 (s, 1H); 8.25 (s, 1H); 7.38-7.21 (m,4H); 6.62-6.60 (d, J=5.1 Hz, 1H); 5.98-5.93 (m, 1H); 5.50 (s, 2H);4.52-4.43 (m, 3H); 4.25-4.10 (m, 2H); 3.31 (s, 3H); 3.21-3.08 (m, 1H);3.05-2.95 (m, 1H); 2.79-2.69 (m, 1H); 2.15-2.03 (m, 1H).

Example 43((2R,3S,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-67) Step a:(2R,3S,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diol

Adenine 9-β-D-arabinofuranoside (0.25 g, 0.936 mmol) was stirred in DMF(2.5 mL) and cooled to 0° C. Imidazole (0.143 g, 2.1 mmol) was addedfollowed by the dropwise addition of triisopropylsilyl chloride (2.89 g,1.49 mmol). The reaction was stirred for seven hours then diluted withwater and extracted using ethyl acetate (3×). The organic layer wasdried (Na₂SO₄), filtered and concentrated. The clear oil was placed onhigh vacuum overnight and used as is (0.780 g, 98%) based on two (0.25g) reactions.

LCMS: R.t. 1.53 min ES+ 424 (formic acid standard)

Step b:(2R,3S,4R,5R)-2-(6-Amino-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diyldiacetate

(2R,3S,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diol(0.858 g, 2.03 mmol) was stirred in pyridine (6 mL) and cooled to 0° C.Acetic anhydride (0.456 g, 0.42 mL) was added dropwise followed by acatalytic amount of dimethylaminopyridine. The reaction was stirred fortwo hours, poured into saturated sodium bicarbonate and extracted withethyl acetate (3×). The organic layer was washed with water, dried(Na₂SO₄), filtered and concentrated. The clear oil was purified by flashchromatography (25-100% ethyl acetate/hexanes) to give product (0.605 g,59%).

LCMS: R.t. 1.94 min ES+ 508 (formic acid)

Step c:(2R,3S,4R,5R)-2-(6-Bromo-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diyldiacetate

(2R,3S,4R,5R)-2-(6-Amino-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diyldiacetate (0.605 g, 1.19 mmol) was dissolved in dibromomethane (24 mL).Trimethylsilyl bromide (0.17 mL, 1.35 mmol) was added dropwise followedby tert-butylnitrite (0.97 mL, 8.12 mmol). The orange solution wasstirred for 2.5 hours then slowly poured into a 1:1 mixture of saturatedsodium bicarbonate and dichloromethane and extracted. The pale yelloworganic layer was washed with water and brine, dried (Na₂SO₄), filteredand concentrated. The yellow solid was purified by flash chromatographyeluting with 25% ethyl acetate/hexanes to give the title compound as ayellow solid (0.402 g, 52%).

LCMS: R.t. 2.53 min ES+ 572 (formic acid)

Step d:(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3,4-diyldiacetate

(2R,3S,4R,5R)-2-(6-Bromo-9H-purin-9-yl)-5-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3,4-diyldiacetate (0.402 g, 0.703 mmol) was stirred in ethanol (10 mL) andS-(+)-1-aminoindan (0.14 mL, 1.06 mmol) was added followed bytriethylamine (0.2 mL, 1.41 mmol). The reaction mixture was heated atovernight. The brown solution was concentrated and purified by flashchromatography, eluting with 10 to 35% ethyl acetate/hexanes to give thetitle compound as a white solid (0.142 g) and deacylated product (0.161g, 37%).

LCMS: R.t. 2.61 min ES+ 624 (formic acid)

Step e:(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diyldiacetate

(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3,4-diyldiacetate (0.305 g, 0.49 mmol) was stirred in pyridine (2 mL) andtetrahydrofuran (2 mL). Hydrofluoric acid in pyridine (2.0 M) was added(15 drops) and the reaction was stirred at room temperature for thirtyminutes. The reaction was quenched using saturated sodium bicarbonatethen extracted using ethyl acetate (3×10 mL). The organic layer wasdried (Na₂SO₄), filtered and concentrated. The brown residue waspurified by column chromatography (30-50% ethyl acetate/hexanes followedby ethyl acetate) to give the title compound as a white solid (0.188 g,82%).

LCMS: R.t. 1.49 min ES+ 468 (formic acid standard)

Step f:(2R,3R,4S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3,4-diyldiacetate

(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diyldiacetate (0.188 g, 0.40 mmol) was stirred in anhydrous methylenechloride (0.6 mL) cooled to 0° C. Triethylamine (0.081 mL, 0.80 mmol)was added followed by the dropwise addition of a 2 N solution ofchlorosulfonamide in acetonitrile (0.6 mL). The yellow solution wasconcentrated after one hour. The residue was purified by columnchromatography using 0-5% methanol/methylene chloride concentrated togive the title compound as a yellow solid (0.104 g, 48%).

LCMS: R.t. 1.49 min ES+ 547 (formic acid)

Step g:((2R,3S,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-67)

(2R,3R,4S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3,4-diyldiacetate (0.104 g, 0.19 mmol) was stirred in a 7 N solution ofammonia/methanol as described in Example 41, step e. The product waspurified on a prep plate using 10% methanol/methylene chloride asdeveloping solvent (0.018 g, 20%).

LCMS: R.t. 1.38 min ES+ 463 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.28 (bs, 1H); 8.18-8.06 (bs, 2H); 7.59(bs, 1H); 7.30-7.07 (m, 4H); 5.95 (bs, 1H); 5.80 (bs, 1H); 5.75 (bs,1H); 4.38-4.26 (m, 4H); 4.18 (bs, 2H); 4.05 (bs, 1H); 3.87 (q, J=7.0 Hz,1H); 3.10-2.97 (m, 1H); 2.91-2.78 (m, 1H).

Example 44((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methylsulfamate (I-56) Step a:[(3aR,4R,6R,6aR)-6-(6-Amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4d]-[1,3]-dioxol-4-yl]methyl acetate

Using essentially the same procedure as described in 43, step b,2′,3′-isopropylidene adenine (10 g 32.5 mmol)) was reacted with aceticanhydride to give the product as a white solid (7.65 g, 67%).

LCMS: R.t. 1.03 min ES+ 350 (formic acid standard)

Step b:[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate

The title compound was prepared using essentially the same procedure asdescribed in Example 43, step c. The product was purified by flashchromatography (25-50% ethyl acetate/hexanes) to give a yellow foam(1.621 g, 69%).

LCMS: R.t. 1.50 min ES+ 413, 415 (formic acid)

Step c:((3aR,4R,6R,6aR)-2,2-Dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylacetate

[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (0.1 g, 0.242 mmol), 3-(1-H-pyrazole-1-yl)phenylboronic acid(0.137 g, 0.726 mmol), potassium phosphate (0.154 g, 0.726 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexdichloromethane (1:1) (0.040 g, 0.048 mmol) were placed in an oven-driedmicrowave vial and degassed with argon. Anhydrous dioxane (1.5 mL) wasadded and the reaction was heated to 150° C. for ten minutes in themicrowave. The mixture was filtered through a pad of Celite washing withdichloromethane then concentrated. The residue was taken up indichloromethane and purified on a prep plate using 60% ethylacetate/hexanes as developing solvent to give the title compound as ayellow solid (0.061 g 53%).

LCMS: R.t. 1.84 min ES+ 477 (formic acid)

Step d:((3aR,4R,6R,6aR)-2,2-Dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol

Using essentially the same procedure as Example 43, step g,((3aR,4R,6R,6aR)-2,2-dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methylacetate (0.217 g, 0.46 mmol) was deprotected and purified by flashchromatography (30-65% ethyl acetate/hexanes) to give the title compoundas a white solid (0.209 g).

LCMS: R.t. 1.67 min ES+ 435 (formic acid)

Step e:((3aR,4R,6R,6aR)-2,2-Dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate

Using essentially the same procedure as Example 43, step f,((3aR,4R,6R,6aR)-2,2-dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methanol(0.2 g, 0.46 mmol) was reacted with chlorosulfonamide, as described inExample 43, step f, and the product was purified by flash chromatographyusing 40-75% ethyl acetate/hexanes to give the title compound as ayellow solid (0.208, 88%).

LCMS: R.t. 1.63 min ES+ 514 (formic acid)

Step f:((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methylsulfamate (I-56)

((3aR,4R,6R,6aR)-2,2-Dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (0.207 g, 0.439 mmol) was stirred in trifluoroaceticacid/water (9:1, 3 mL) for 1.5 hours then concentrated. The residue wastaken up in methanol and purified on a prep plate using 10%methanol/methylene chloride as developing solvent to give the product asa pale yellow solid (0.093 g, 45%).

LCMS: R.t. 1.30 min ES+ 474 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 9.28 (s, 1H); 9.04 (s, 1H); 8.84 (s, 1H);8.76 (d, J=8.2 Hz, 1H); 8.55 (ds, J=2.4 Hz, 1H); 8.01 (dd, J=1.5 Hz,J=9.5 Hz, 1H); 7.79 (ds, J=1.5 Hz, 1H); 7.78 (t, J=8.0 Hz, 1H); 7.60 (s,2H); 6.57 (t, J=2.3 Hz, 1H); 6.35 (bs, 1H); 6.12 (d, J=5.1 Hz, 1H); 4.68(t, J=4.9 Hz, 1H); 4.32-4.17 (m, 4H).

Example 45((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[3-(trifluoromethyl)phenyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methylsulfamate (I-57) Step a:((3aR,4R,6R,6aR)-2,2-Dimethyl-6-{6-[3-(trifluoromethyl)phenyl]-9H-purin-9-yl}-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylacetate

[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (0.60 g, 1.45 mmol), 3-(trifluoromethyl)phenylboronic acid(0.414 g, 2.18 mmol), palladium(II) acetate (0.033 g, 0.145 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.136 g, 0.218mmol), and potassium phosphate (0.617 g, 2.91 mmol) were placed in anoven dried flask and degassed using argon. Anhydrous dioxane (9 mL) wasadded and the reaction was heated to 90° C. overnight. The mixture wasfiltered through a pad of Celite washing with methylene chloride. Thefiltrate was concentrated and purified by flash chromatography using25-40% ethyl acetate/hexanes. Relevant fractions were collected andconcentrated to give the product (0.224 g, 32%).

LCMS: R.t. 2.05 min ES+ 479 (formic acid)

Step b:((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[3-(trifluoromethyl)phenyl]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methylsulfamate (I-57)

The product was prepared following the procedure described in Example44, steps d-f.

LCMS: R.t. 1.56 min ES+ 476 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 9.19 (s, 1H); 9.11 (d, J=7.9 Hz, 1H); 9.09(s, 1H); 8.89 (s, 1H); 7.97 (d, J=7.9 Hz, 1H); 7.88 (t, J=7.8 Hz, 1H);7.60 (bs, 1H); 6.15 (d, J=5.1 Hz, 1H); 5.71 (d, J=5.8 Hz, 1H); 5.51 (bs,1H); 4.70 (t, J=4.7 Hz, 1H); 4.35-4.23 (m, 4H).

Example 46[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl]methyl sulfamate (I-62) Step a:[(3aR,4R,6R,6aR)-2,2-Dimethyl-6-(6-phenyl-9H-purin-9-yl)tetrahydrofuro[3,4-d]-[1,3]-dioxol-4-yl]methyl acetate

Using essentially the same procedure as Example 45, step a,[(3aR,4R,6R,6aR)-6-(6-bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate (0.60 g, 1.45 mmol) was reacted with phenylboronic acid (0.22 g,1.8 mmol) and the product was purified by flash chromatography (20-50%ethyl acetate/hexanes) (0.322 g, 44° A).

LCMS: R.t. 1.79 min ES+ 411 (formic acid)

Step b:[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl]-methyl sulfamate (I-62)

The product was prepared following the procedure described in Example44, steps d-f.

LCMS: R.t. 1.20 min ES+ 408 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 9.02 (s, 1H); 8.82-8.84 (m, 3H); 7.65-7.57(m, 4H); 6.15 (d, J=5.2 Hz, 1H); 5.71 (d, J=5.8 Hz, 1H); 5.49 (bs, 1H);4.72 (q, J=5.2 Hz, 1H); 4.34-4.19 (m, 4H).

Example 47{(2R,3S,4R,5R)-5-[6-(3,5-Dimethylisoxazol-4-yl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-66) Step a:{(3aR,4R,6R,6aR)-6-[6-(3,5-Dimethylisoxazol-4-yl)-9H-purin-9-yl]-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylacetate

Using essentially the same procedure as Example 45, step a,[(3aR,4R,6R,6aR)-6-(6-bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate (0.60 g, 1.45 mmol) was reacted with3,5-dimethylisoxazol-4-boronic acid (0.25 g, 1.88 mmol) at 90° C. for2.5 days and the product was purified by flash chromatography (10-40%ethyl acetate/hexanes) (0.180 g, 22%).

LCMS: R.t. 1.50 min ES+ 430 (formic acid)

Step b:{(2R,3S,4R,5R)-5-[6-(3,5-Dimethylisoxazol-4-yl)-9H-purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl}methylsulfamate (I-66)

The product was prepared following the procedures described in Example44, steps d-f.

LCMS: R.t. 1.09 min ES+ 427 (formic acid)

¹H NMR (400 MHz, CD₃OD): δ 9.00 (s, 1H); 8.67 (s, 1H); 6.26 (d, J=5.0Hz, 1H); 4.54-4.36 (m, 4H); 3.36 (s, 1H); 2.63 (s, 3H) 2.46 (s, 3H).

Example 48((2R,3R,4R,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methylsulfamate (I-54)

The product was prepared following an analogous sequence of reactions asdescribed in Example 42.

LCMS: R.t. 1.38 min ES+ 477 (formic acid)

¹H NMR (300 MHz, CDCl₃): δ 8.42 (bs, 1H); 7.93 (s, 1H); 7.76 (bs, 1H);7.58 (s, 1H); 6.17 (bs, 1H); 6.01 (d, J=3.6 Hz, 1H); 5.93 (bs, 1H); 5.49(bs, 2H); 4.61-4.44 (m, 3H); 3.49 (m, 1H); 3.10 (s, 1H); 3.08-2.89 (m,2H); 2.54 (m, 1H); 2.03-1.93 (m, 1H).

Example 492-((2R,3S,4R,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide(I-31) Step a:[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbaldehyde

To a suspension of Dess-Martin periodinane (16.42 g, 0.03872 mol) inanhydrous methylene chloride (88.0 mL) cooled in an ice/water bath wasadded[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol(11.50 g, 0.03520 mol) in methylene chloride (200 mL). The reaction wasstirred under an atmosphere of nitrogen and allowed to warm to ambienttemperature. After 2 hours, a further portion of Dess-Martin periodinane(1.00 g, 0.00236 mol) was added. After 3 hours, a solution (200 mL) ofsodium thiosulfate (50 g in 200 mL of saturated aqueous sodiumbicarbonate) was added and the mixture stirred for 10 min. The aqueouswas extracted 2×250 mL methylene chloride and 8×50 mL of chloroform. Thecombined organics were washed with water and dried over magnesiumsulfate and concentrated in vacuo to dryness. The residue was taken upin dry toluene (200 mL) and concentrated in vacuo, and then taken up indry methylene chloride and concentrated in vacuo to yield the product asa foam (9.83 g, 86%).

Step b: (Diethoxyphosphoryl)-methanesulfonic acid ethyl ester

To a solution of methanesulfonic acid, ethyl ester (11.00 mL, 0.1068mol) in THF (200.0 mL, 2.466 mol) at −78° C. was added 2.500 M ofn-butyllithium in hexane (50.00 mL) over 15 minutes and the mixture wasstirred for 20 minutes. Phosphorochloridic acid, diethyl ester (10.0 mL,0.0694 mol) was added to the mixture at −78° C. The mixture was stirredfor 3.5 hours, allowing to warm to 0° C. The reaction was quenched with5M ammonium chloride in water (100 mL) and the mixture was concentratedin vacuo to remove THF. The aqueous was extracted with EtOAc (2×150 mL)and the organics were combined and concentrated in vacuo. The productwas purified by flash chromatography (0 to 100% EtOAc/Hexanes) to yieldthe product as an oil (9.07 g, 50%+10.4 g of a mixed fraction).

Step c: Ethyl2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]ethenesulfonate

To a solution of (diethoxy-phosphoryl)-methanesulfonic acid ethyl ester(7.991 g, 0.03070 mol) in THF (100 mL), at −78° C. under an atmosphereof nitrogen, was added dropwise 2.5M n-butyllithium in hexane (13 mL),and the solution was stirred for 30 minutes. Freshly prepared6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxole-4-carbaldehyde(13.10 g, 0.03026 mol) in THF (100 mL) was added over 15 min at −78° C.The reaction was allowed to slowly warm to −10° C. over 4 hours withstirring. The reaction was quenched with water (400 mL) and 5M ammoniumchloride in water (100 mL) and extracted with methylene chloride (600mL). The organic phase was concentrated in vacuo and the residue waspurified by flash chromatography (30 to 100% EtOAc:hexanes) to yield theproduct as a foam (10.5 g, 81%).

Step d: Ethyl2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]ethanesulfonate

Ethyl2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl]ethenesulfonate(10.500 g, 0.024370 mol) was dissolved in ethanol (200 mL, 3 mol) in a1-necked round-bottom flask. Sodium borohydride (507.1 mg, 0.01340 mol)was added in 2 portions, 10 min apart. The reaction was stirred for afurther 15 min at 25° C. The reaction was diluted with water (400 mL)and 5M ammonium chloride in water (50 mL) and was concentrated in vacuoto remove most of the ethanol. The aqueous residue was extracted withmethylene chloride (2×250 mL) and the organic phase was concentrated invacuo to yield crude product (9.83 g).

Step e: Tetrabutyl-ammonium2-[(3aR,4R,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethanesulfonate

Ethyl2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl]ethanesulfonate(1.8900 g, 0.0043661 mol) and tetra-n-butylammonium iodide (1.613 g,0.004366 mol) were dissolved in acetone (70.00 mL) and heated to refluxfor 26 h. The reaction mixture was cooled and concentrated in vacuo todryness to yield crude product (2.84 g).

Step f:2-[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]ethanesulfonylchloride

Tetrabutyl-ammonium2-[(3aR,4R,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethanesulfonate(250.0 mg, 0.0003481 mol) was dissolved in methylene chloride (5.00 mL,0.0780 mol) and N,N-dimethylformamide (100.0 μL, 0.001292 mol). Thionylchloride (228 μL, 0.00313 mol) was added and the reaction was stirred at0° C. for 45 minutes, concentrated in vacuo to dryness and followed byazeotroping with toluene. The residue was purified by flashchromatography (10% THF in DCM) to yield product (115 mg, 78%).

Step g:2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl]-ethanesulfonamide

2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-ethanesulfonylchloride (100.0 mg, 0.0002362 mol) was dissolved inN,N-Dimethylformamide (2.0 mL). 7.00 M of Ammonia in Methanol (0.500 mL)was added at 0° C. and the mixture was stirred for 30 minutes, allowingto warm to room temperature. The reaction was concentrated in vacuo andthe residue was diluted with brine and extracted with EtOAc. The organicphase was brine washed, water washed and evaporated. The residue waspurified by flash chromatography (0 to 100% EtOAc/Hexanes) to yield theproduct (40 mg, 42%).

Step h:2-[(3aR,4R,6R,6aR)-6-(6-(Indan-1-ylamino)-purin-9-yl)-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide

2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide(45.0 mg, 0.000111 mol), (S)-(+)-1-aminoindane (20.0 μL, 0.000156 mol)and N,N-diisopropylethylamine (24.0 μL, 0.000138 mol) were dissolved inethanol (1.25 mL, 0.0214 mol) and reacted in a microwave at 140° C. for10 minutes. The mixture was then concentrated in vacuo and used crude inthe next step.

Step i:2-((2R,3S,4R,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide(I-31)

Trifluoroacetic acid (3.60 mL, 0.0467 mol) was added to water (0.40 mL,0.022 mol) and the mixture was added to2-[(3aR,4R,6R,6aR)-6-(6-(indan-1-ylamino)-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide(crude, 0.000111 mol). The reaction was left to stand (with occasionalshaking) for 25 minutes. The reaction was concentrated in vacuo todryness and the residue purified by preparative HPLC to yield the titlecompound 23 mg.

LCMS: R.t. 1.31 min ES+ 461 (formic acid)

¹H-NMR (300 MHz, CD₃OD): δ 8.45 (s, 1H), 8.32 (s, 1H), 7.35 (m, 4H),6.10 (d, 1H, J=4.6 Hz), 4.93 (m, 1H), 4.41 (t, 1H, J=5.3 Hz), 4.26 (dd,1H, J=6.2 Hz, J=12.2 Hz), 3.35 (td, 2H, J=6.8 Hz, J=13.8 Hz), 3.22 (ddd,1H, J=3.8 Hz, J=8.7 Hz, J=15.9 Hz), 3.07 (td, 1H, J=8.2 Hz, J=16.1 Hz),2.81 (m, 1H), 2.43 (dd, 2H, J=7.2 Hz, J=15.2 Hz), 2.15 (ddd, 1H, J=8.4Hz, J=12.7 Hz, J=16.1 Hz).

Example 502-((2R,3S,4R,5R)-5-{6-[(4-Chlorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxy-tetrahydrofuran-2-yl)ethanesulfonamide(I-50)

2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamidewas reacted with 4-chlorobenzylamine as described in Example 43, step h,and deprotected as described in 43, step i.

LCMS: R.t. 1.25 min ES+ 469 (formic acid standard)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.47 (br, 1H), 8.36 (1H), 8.20 (s, 1H),7.35 (br, 4H), 6.78 (br, 2H), 5.86 (d, 1H, J=4.6 Hz), 4.65 (m, 2H), 4.14(t, 1H, J=4.7 Hz), 3.95 (dd, 1H, J=6.0 Hz, J=11.3 Hz), 3.16 (d, 1H,J=0.7 Hz), 3.03 (dd, 2H, J=5.5 Hz, J=9.8 Hz), 2.09 (m, 2H).

Example 512-((2R,3S,4R,5R)-5-{6-[(3,5-Difluorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide(I-49)

2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamidewas reacted with 3,5-difluorobenzylamine as described in Example 43,step h, and deprotected as described in 43, step i.

LCMS: R.t. 1.22 min ES+ 471 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.50 (br, 1H), 8.39 (s, 1H), 8.22 (s, 1H),7.06 (ddd, 3H, J=2.5 Hz, J=5.8 Hz, J=12.2 Hz), 6.77 (s, 2H), 5.87 (d,1H, J=4.8 Hz), 4.72 (m, 2H), 4.66 (t, 1H, J=5.0 Hz), 4.14 (t, 1H, J=5.0Hz), 3.96 (dd, 1H, J=6.2 Hz, J=11.5 Hz), 3.04 (t, 2H, J=4.8 Hz), 2.10(td, 2H, J=4.8 Hz, J=9.6 Hz).

Example 522-((2R,3S,4R,5R)-5-{6-[(Diphenylmethyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide(I-51)

2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamidewas reacted with α-phenylbenzylamine as described in Example 49, step h,and deprotected as described in Example 49, step i.

LCMS: R.t. 1.42 min ES+ 511 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.73 (br, 1H), 8.40 (s, 1H), 8.24 (s, 1H),7.43 (d, 4H, J=7.4 Hz), 7.32 (t, 4H, J=7.4 Hz), 7.23 (t, 2H, J=7.1 Hz),6.78 (s, 2H), 5.87 (d, 1H, J=4.8 Hz), 4.66 (dd, 1H, J=4.3 Hz, J=8.8 Hz),4.14 (m, 1H), 3.95 (dd, 1H, J=6.2 Hz, J=11.4 Hz), 3.03 (dd, 2H, J=5.4Hz, J=9.9 Hz), 2.09 (m, 2H).

Example 532-[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]ethanesulfonamide(I-32)

2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]ethanesulfonamidewas reacted with (1R,2S) 1-amino-2-hydroxyindane as described in Example49, step h, and deprotected as described in 49, step i.

LCMS: R.t. 1.03 min ES+ 477 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.43 (s, 1H), 8.35 (s, 1H), 7.21 (m, 4H),6.80 (s, 2H), 5.91 (d, 1H, J=4.7 Hz), 4.68 (t, 1H, J=5.0 Hz), 4.59 (d,1H, J=4.5 Hz), 4.17 (d, 1H, J=4.3 Hz), 3.99 (dd, 1H, J=6.1 Hz, J=11.3Hz), 3.16 (m, 1H), 3.06 (dd, 2H, J=5.3 Hz, J=9.6 Hz), 2.91 (d, 1H,J=16.0 Hz), 2.12 (m, 2H).

Example 542-{(2R,3S,4R,5R)-5-[6-(Bicyclo[2.2.1]hept-2-ylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}ethanesulfonamide(I-52)

2-[(3aR,4R,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamidewas reacted with (exo)-1-amino norbornane as described in Example 49,step h, and deprotected as described in 49, step i.

LCMS: R.t. 1.06 min ES+ 439 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.41 (s, 1H), 8.27 (s, 1H), 6.78 (br, 2H),5.88 (d, 1H, J=4.6 Hz), 4.65 (q, 1H, J=4.3 Hz), 4.14 (t, 1H, J=3.5 Hz),3.97 (dd, 2H, J=5.8 Hz, J=11.2 Hz), 3.04 (dd, 2H, J=5.1 Hz, J=9.3 Hz),2.24 (m, 2H), 2.10 (m, 2H), 1.66 (m, 3H), 1.47 (q, 2H, J=8.1 Hz), 1.27(t, 1H, J=10.6 Hz), 1.12 (dd, 2H, J=7.9 Hz, J=14.9 Hz).

Example 55[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-14) Step a:(2R,3R,4R,5R)-2-(6-{[(1R,2S)-2-(Acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diyldiacetate

To a suspension of 6-chloro-β-D-ribofuranosylpurine (0.573 g, 0.002 mol)in ethanol (20 mL) was added (1R,2S)-1-amino-2-indanol (0.33 g, 0.0022mol) and diisopropylethylamine (0.38 mL, 0.0022 mol) and the reactionmixture heated to reflux for 4 h. The mixture was collected andconcentrated in vacuo to dryness and dissolved in pyridine (20 mL).4,4′-dimethoxytrityl chloride (0.74 g, 0.0022 mol) was added and thereaction stirred overnight.

The reaction mixture was cooled (ice bath) and acetic anhydride (0.8 mL,0.008 mol) added dropwise. The reaction was stirred for 90 min allowingto warm to room temperature. The reaction was concentrated in vacuo,taken up in ethyl acetate (50 mL), washed with water (2×25 mL), driedand concentrated in vacuo to dryness.

The residue was taken up in methylene chloride (100 mL) andtriisopropylsilane (3.0 mL, 0.015 mol) was added followed bytrifluoroacetic acid (1.0 mL, 0.013 mol) and the reaction stirred for 10min and concentrated in vacuo.

Flash chromatography (methylene chloride:ethyl acetate 30 to 70%) gaveproduct (0.25 g) contaminated with over acylated material.

LCMS: R.t. 1.75 min ES+ 526 (ammonium acetate).

Step b:(2R,3R,4R,5R)-2-(6-{[(1R,2S)-2-(acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)-5-{[(aminosulfonyl)oxy]methyl}tetrahydrofuran-3,4-diyldiacetate

(2R,3R,4R,5R)-2-(6-{[(1R,2S)-2-(acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diyldiacetate (0.225 g, 0.0003 mol) was reacted with chlorosulfonamide asdescribed in Example 43 step f. The product was purified by flashchromatography (methylene chloride:ethyl acetate 20 to 60%) (0.11 g,60%).

LCMS: R.t. 1.64 min ES+ 605 (ammonium acetate).

Step c:[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-14)

(2R,3R,4R,5R)-2-(6-{[(1R,2S)-2-(acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-9H-purin-9-yl)-5-{[(aminosulfonyl)oxy]methyl}tetrahydrofuran-3,4-diyldiacetate was stirred in 7M ammonia in methanol (2 mL) for 8 hours andthe reaction concentrated in vacuo. The product was purified by HPLC togive 0.024 g, 30% yield.

LCMS: R.t. 1.21 min ES+ 479 (ammonium acetate).

¹H-NMR (300 MHz, CD₃OD): δ 8.46 (s, 1H), 8.37 (s, 1H), 7.38-7.45 (m,4H), 6.23 (m, 1H), 5.91 (br), 4.71-4.91 (m, 3H), 4.41-4.60 (m, 4H), 3.30(m, 1H), 3.07-3.17 (m, 2H), 2.90 (m, 1H).

Example 56((2R,3R,4R,5R)-5-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methylsulfamate (I-55) Step a:(2R,3R,4R,5R)-2-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol

(2R,3R,4R,5R)-5-[(Benzoyloxy)methyl]-2-(6-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-3,4-diyldibenzoate was prepared according to the method described by M. Wolfe,J. Org. Chem. (1997), 62:1754 and P. Franchetti, J. Med. Chem. (1998),41:1708.

A solution of(2R,3R,4R,5R)-5-[(benzoyloxy)methyl]-2-(6-chloro-9H-purin-9-yl)-3-methyltetrahydrofuran-3,4-diyldibenzoate (0.35 g, 0.57 mmol), (S)-(+)-1-aminoindane (0.32 g, 2.3mmol), N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in ethanol (3 mL,0.05 mol) was reacted in a microwave at 150° C. for 15 min.

The reaction mixture was transferred to a pressure tube and the solventremoved by bubbling nitrogen through. The residue was taken up inmethanolic ammonia (7M)(10.0 mL) and the reaction mixture was heated for5 h at 45° C. The reaction mixture was cooled and concentrated in vacuo.Flash chromatography (6% methanol in chloroform) gave product, 0.22 g,97%.

LCMS: R.t. 1.3 min ES+ 369 (ammonium acetate).

Step b:((3aR,4R,6R,6aR)-6-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-2,2,6a-trimethyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methanol

A solution of(2R,3R,4R,5R)-2-(6-((S)-2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol(0.21 g, 0.53 mmol), p-toluenesulfonic acid monohydrate (0.10 g, 0.53mmol), 2,2-dimethoxypropane (1.0 mL, 8.1 mmol) in acetone (5 mL) wasstirred for 8 h. The reaction mixture was concentrated in vacuo andpartitioned between ethyl acetate (25 mL) and saturated sodiumbicarbonate (15 mL), the aqueous was extracted with ethyl acetate andthe organic phases combined, dried (MgSO₄) and concentrated in vacuo.Flash chromatography (2% methanol in chloroform) gave the title compound0.155 g, 67% yield.

LCMS: R.t. 1.74 ES+ 438 (ammonium acetate).

Step c:((2R,3R,4R,5R)-5-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methylsulfamate (I-55)

To a solution of((3aR,4R,6R,6aR)-6-(6-((S)-2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-2,2,6a-trimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.12 g, 0.27 mmol), N,N-diisopropylethylamine (100 μL, 0.8 mmol) inacetonitrile (2.0 mL) was added a solution of chlorosulfonamide inacetonitrile (2.0 M) (0.4 mL) dropwise. The reaction was stirred for 3 hand evaporated to dryness.

Flash chromatography (4% methanol in methylene chloride) gave theprotected sulfamate 70 mg.

LCMS: R.t. 1.75 ES+ 517 (ammonium acetate).

The protected sulfamate was dissolved in a solution of trifluoroaceticacid in water (9:1, 3.0 mL) and stirred for 20 min. The reaction mixturewas concentrated in vacuo and methanol added and again concentrated invacuo. The product was purified by HPLC.

LCMS: R.t. 1.39 min ES+ 477 (ammonium acetate).

¹H-NMR (300 MHz, CD₃OD): δ 8.28 (s, 1h), 8.19 (s, 1H), 7.11-7.25 (m,4H), 6.08 (s, 1H), 4.52 (dd J 11.2 Hz, 2.0 Hz, 1H) 4.42 (dd J 11.2, 3.3Hz, 1H), 4.15-4.21 (m, 2H), 2.98-3.07 (m, 1H), 2.83-2.93 (m, 1H),2.56-2.66 (m, 1H), 1.90-2.03 (m, 1H), 0.90 (s, 3H).

Example 57((2R,3S,4R,5R)-5-{2-Chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-3) Step a: (2-Chloro-9H-purin-6-yl)-(S)-indan-1-yl-amine

(S)-(+)-1-Aminoindane (266.0 mg, 2.0 mmol), 2,6-dichloropurine (380 mg,2.0 mmol) and N,N-diisopropylethylamine (380 μL, 2.2 mmol), weredissolved in Ethanol (4.0 mL) and reacted in a microwave at 120° C. for600 s. A yellow solid formed which was filtered, washed with ethanol (20mL) and dried to give the title compound 0.455 g, 80% yield.

LCMS: R.t. 1.77 ES+ 286, 288 (ammonium acetate).

Step b:(2S,3R,4R,5R)-2,4-Diacetoxy-5-sulfamoyloxymethyl-tetrahydro-furan-3-ylacetate

The title compound was prepared from(2S,3R,4R,5R)-2,4-diacetoxy-5-hydroxymethyl-tetrahydro-furan-3-ylacetate by reaction with chlorosulfonamide following a procedureanalogous to that described in Example 43, step f.

Step c:(2R,3R,4R,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{2-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3,4-diyldiacetate

To a suspension of(2S,3R,4R,5R)-2,4-diacetoxy-5-sulfamoyloxymethyl-tetrahydro-furan-3-ylacetate (200 mg, 0.6 mmol),(2-chloro-9H-purin-6-yl)-(S)-indan-1-yl-amine (180 mg, 0.62 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (420 μL, 2.8 mmol) in acetonitrile (8mL) cooled by an ice/water bath was added trimethylsilyltrifluoromethanesulfonate (610 μL, 3.4 mmol) dropwise. The reactionbecame clear and after min the reaction was heated to 60° C. for 4 h.The reaction was allowed to cool, diluted with ethyl acetate (30 mL) andwashed with saturated sodium bicarbonate solution, HCl aq (0.05M), andbrine. The organic was dried (MgSO₄) and concentrated in vacuo.

Flash chromatography (2% MeOH in methylene chloride) gave the product,105 mg, 30% yield.

Step d:((2R,3R,4R,5R)-5-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl)methylsulfamate (I-55)

To a solution of(2R,3R,4R,5R)-2-{[(aminosulfonyl)oxy]methyl}-5-{2-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3,4-diyldiacetate (90 mg, 2.2 mmol) in methanol (2.0 mL) was added a solution ofammonia in methanol (7M), (2.0 mL) and the reaction mixture was stirredfor 30 min. LCMS showed complete reaction. The reaction was concentratedin vacuo to dryness. Purification by preparative HPLC gave product, 23mg, 30% yield.

LCMS: R.t. 1.76 ES+ 497, 499 (ammonium acetate).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.75 (d, J=8.6 Hz, 1H, exchange D₂O), 8.33(s, 1H), 7.60 (br.s, 1H, exchange D₂O), 7.11-7.27 (m, 4H), 5.90 (d J 5.3Hz, 1H), 5.76-5.86 (m, 1H), 5.70 (br.s, 1H, exchange D₂O), 5.51 (br.s,1H, exchange D₂O), 4.46-4.57 (m, 1H), 4.17-4.30 (m, 4H), 3.25-3.30 (m,1H), 2.73-2.92 (m, 1H), 2.03-2.22 (m, 1H).

Example 58(R)-1-((2S,3S,4R,5R)-5-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)ethylsulfamate (I-58) Step a:1-((3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]-dioxol-4-yl)ethanol

To a suspension of Dess-Martin periodinane (1.4 g, 3.3 mmol) inmethylene chloride (8 mL), cooled in an ice/water bath, was addeddropwise a solution of((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(0.978 g, 3.0 mmol) in methylene chloride (10 mL). The reaction wasallowed to warm to ambient temperature while stirring for 2 h.

A solution of sodium thiosulfate (25%) in sat. sodium bicarbonate (25mL) was added and the mixture stirred for 15 min and extracted withmethylene chloride (3×15 mL). The organic was dried (MgSO₄) andevaporated to give a colorless foam, 0.66 g.

To a solution of the aldehyde (0.65 g, 2.0 mmol) in anhydrous THF (20mL) at −78° C. was added dropwise a 3.0 M solution of methylmagnesiumbromide in diethylether (1.2 mL, 4.0 mmol) and the reaction was allowedto warm to −20° C. over 2 h while being stirred under a stream ofnitrogen.

The reaction was quenched with saturated ammonium chloride solution (20mL) containing acetic acid (0.5 mL) and extracted with ethyl acetate(3×50 mL).

Flash chromatography (3:2 methylenechloride: EtOAc) gave the titlecompound (0.32 g, 27% yield).

LCMS: R.t. 1.36 ES+ 339, 341 (ammonium acetate).

Step b:(R)-1-((3aR,4R,6R,6aR)-6-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)ethanol

(S)-(+)-1-Aminoindane (40.0 mg, 0.3 mmol),1-((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethanol(68 mg, 0.2 mmol) and triethylamine (40 μL, 0.3 mmol), were dissolved inethanol (2.0 mL) and reacted in a microwave at 140° C. for 600 s. Thereaction mixture was concentrated in vacuo.

Flash chromatography (4:1 to 2:1 methylene chloride:EtOAc) gave product,73 mg, 83% yield.

LCMS: R.t. 1.83 ES+ 438 (ammonium acetate).

Step c:(R)-1-((2S,3S,4R,5R)-5-(6-((S)-2,3-Dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)ethylsulfamate (I-58)

To a stirred solution of(R)-1-((3aR,4R,6R,6aR)-6-(6-((S)-2,3-dihydro-1H-inden-1-ylamino)-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethanol(60 mg, 0.136 mmol) and triethylamine (0.03 mL) in DMF at 0° C. wasadded a solution of chlorosulfonamide (2.0 M in MeCN) dropwise (0.1 mL)and the reaction was allowed to warm to ambient temperature while beingstirred under an inert atmosphere. A further aliquot ofchlorosulfonamide solution (0.1 mL) and triethylamine (0.03 mL) wereadded and the reaction stirred for 30 min.

The reaction mixture was filtered, the precipitate washed with methylenechloride and the organics combined and concentrated in vacuo.

Flash chromatography (1:2 methylene chloride: EtOAc) gave the protectedsulfamate 35 mg, 83% yield.

LCMS: R.t. 1.81 ES+ 517 (ammonium acetate).

The protected sulfamate (33 mg 0.06 mmol) was dissolved in cold(ice/water bath) TFA:water 9:1 (2 mL) and the reaction allowed to warmto ambient temperature. After 15 min the mixture was concentrated invacuo, the residue taken up in dry methylene chloride (10 mL) andconcentrated in vacuo. This was repeated 3 times to give the titlecompound as a mixture of diastereomers in approx. 3:1 ratio, 30 mg, 98%.

LCMS: R.t. 1.42 ES+ 477 (ammonium acetate).

¹H-NMR (300 MHz, CD₃OD): δ 8.4-8.6 (br. m, 2H), 7.15-7.38 (m, 4H),6.05-6.25 (m, 1H), 4.75-4.85 (m, 1H), 4.60-4.70 (m, 1H), 4.45-4.55 (m,1H), 4.05-4.15 (m, 1H), 3.28-3.35 (m, 1H), 3.07-3.20 (m, 1H), 2.90-3.05(m, 1H), 2.62-2.80 (br., 1H), 2.08-2.20 (m, 1H), 1.45-1.55 (m, 3H).

Example 59N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(4-methoxybenzyl)sulfanyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-40) Step a:(2R,3R,4R,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diyldi-acetate

6-Chloro-9-β-D-ribofuranosylpurine (1.147 g, 0.0040 mol) and4,4′-dimethoxytrityl chloride (1.423 g, 0.0042 mol) were stirred inpyridine (20 mL) at room temperature for 60 h. Acetic anhydride (1.510mL, 0.01600 mol) and 4-dimethylaminopyridine (97.7 mg, 0.000800 mol)were added and the reaction stirred at room temperature for 3 h. Thereaction was concentrated in vacuo and the residue taken up in methylenechloride. The solution was washed twice with HCl (1N) and once withwater, dried over Na₂SO₄ and concentrated in vacuo to obtain an oil. Theproduct was treated with methylene chloride/trifluoroaceticacid/triisopropylsilane 100:2:2 (104 mL) for 20 min. The solution wasconcentrated in vacuo and the residue purified by flash chromatography(DCM/EtOAc 10% to 80%) to obtain the product as a white solid (447 mg,30%).

LCMS: R.t. 1.12 min ES+ 371 (formic acid)

Step b:(2R,3R,4R,5R)-2-{[(Aminosulfonyl)(tert-butoxycarbonyl)amino]methyl}-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyldiacetate

(2R,3R,4R,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diyldi-acetate (425.0 mg, 0.001146 mol), N-Boc-sulfamide (337.4 mg, 0.001720mol) and triphenylphosphine (360.8 mg, 0.001376 mol) were dissolved inethyl acetate (10 mL) under nitrogen and diisopropyl azodicarboxylate(338.6 μL, 0.001720 mol) was added dropwise as a solution in ethylacetate (2 mL). The solution was stirred at room temperature undernitrogen for 3 h. The solution was concentrated in vacuo and the residuepurified by flash chromatography (DCM/EtOAc 10% to 50%) to give product,contaminated with triphenylphosphine oxide (502 mg).

LCMS: R.t 1.49 min ES+ 549 (formic acid)

Step c:(2R,3R,4R,5R)-2-{[(Aminosulfonyl)amino]methyl}-5-(6-chloro-9H-purin-9-yl)-tetrahydrofuran-3,4-diyldi-acetate

(2R,3R,4R,5R)-2-{[(Aminosulfonyl)(tert-butoxycarbonyl)amino]methyl}-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyldi-acetate (502 mg, 0.000914 mol) was treated with trifluoroaceticacid/methylene chloride 1:2 (9 mL) for 45 min. The solution wasconcentrated in vacuo and the residue purified by flash chromatography(DCM/EtOAc 30% to 80%) to obtain the product as a white solid (251 mg,61%).

LCMS: R.t. 1.07 min ES+ 449 (formic acid)

Step d:N-[((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(4-methoxybenzyl)sulfanyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methyl]sulfamide(I-40)

2-{[(Aminosulfonyl)amino]methyl}-5-(6-chloro-9H-purin-9-yl)tetrahydro-furan-3,4-diyldi-acetate (120.0 mg, 0.2674 mmol), p-methoxy-α-toluenethiol (149.0 μL,1.069 mmol) and triethylamine (149.0 μL, 0.001069 mol) were refluxed inethanol (10 mL, 0.2 mol) overnight. After 14h, the reaction wasconcentrated in vacuo. The residue was treated with ammonia 7N in MeOH(3 mL) at room temperature. After 1h, the solution was concentrated invacuo and the residue purified by HPLC to obtain the product as alyophilized powder (66 mg, 51%).

LCMS: R.t. 1.27 min ES+ 483 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.77 (s, 1H), 8.68 (s, 1H), 7.38 (d, 2H,J=8.6 Hz), 7.08 (br s, 1H), 6.87 (d, 2H, J=8.6 Hz), 6.61 (br s, 2H),5.95 (d, 1H, J=6.8 Hz), 4.73 (m, 1H), 4.61 (s, 2H), 4.18 (m, 1H), 4.10(m, 1H), 3.72 (s, 3H), 3.28-3.10 (m, 2H).

Example 60{(2R,3S,4R,5R)-5-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methylsulfamate (I-41) Step a:[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate

[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methanol(1.000 g, 0.003060 mol), pyridine (495.1 μL, 0.006121 mol),4-dimethylaminopyridine (0.0748 g, 0.000612 mol) and acetic anhydride(577.5 μL, 0.006121 mol) were stirred in methylene chloride (20 mL) atroom temperature for 1 h. The solution was diluted with Methylenechloride, extracted with HCl 1N, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography (EtOAc/DCM 0% to25%) to obtain the product (1.129 g, 84%) as an oil.

LCMS: R.t. 1.38 ES+ 477 (formic acid).

Step b:{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyltetrahydro-furo[3,4-d][1,3]-dioxol-4-yl}methylacetate

[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (369 mg, 0.00100 mol) andtetrakis(triphenylphosphine)-palladium(0) (58 mg, 0.000050 mol) weredissolved in tetrahydrofuran (10 mL) at room temperature under nitrogen.0.5 M of 4-fluorobenzyl zinc chloride in tetrahydrofuran (3 mL) wasadded dropwise over 10 min. The solution was stirred under nitrogen atroom temperature for 15 min then heated at 60° C. for 3 h. The reactionwas allowed to cool to r.t then poured on saturated NH₄Cl (10 mL).Saturated Na₂EDTA (10 mL) was added and the solution extracted threetimes with EtOAc. The organics were pooled and extracted twice withsaturated Na₂EDTA then once with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(DCM/EtOAc 10% to 50%) to obtain the product (322 mg, 73%) as an oil.

LCMS: R.t. 1.63 ES+ 443(formic acid).

Step c:{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl}methanol

{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylacetate (307 mg, 0.000694 mol) was treated with 7M ammonia in methanol(5 mL) at room temperature for 2 h. The solution was concentrated andthe residue purified by flash chromatography (DCM/EtOAc 10% to 80%) togive the product as an oil (260 mg, 94%).

LCMS: R.t. 1.43 ES+ 401(formic acid).

Step d:{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl}methylsulfamate

{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methanol(249 mg, 0.000622 mol) and triethylamine (173.4 μL, 0.001244 mol) weredissolved in dry N,N-dimethylformamide (10 mL) under nitrogen and thesolution was cooled in a water/ice bath. A 2M solution ofchlorosulfonamide in acetonitrile (0.0012 mol, 600 μL) was addeddropwise. After 1.5 h, the reaction was quenched with methanol,concentrated in vacuo and the residue was purified by flashchromatography (DCM/EtOAc 30% to 80%) to obtain the product as an oil(262 mg, 88%).

LCMS: R.t. 1.49 ES+ 480(formic acid).

Step e:{(2R,3S,4R,5R)-5-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methylsulfamate (I-41)

{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylsulfamate (252 mg, 0.000526 mol) was treated with trifluoroaceticacid/water 4:1 (5 mL) for 15 min at room temperature The solution wasconcentrated to dryness and the residue purified by HPLC to give theproduct as a lyophilized powder (106 mg, 46%).

LCMS: R.t. 1.15 ES+ 440(formic acid).

¹H-NMR (300 MHz, d₆-DMSO+D₂O): δ 8.85 (s, 1H), 8.73 (s, 1H), 7.40 (dd,2H, J=8.8 Hz, J=5.6 Hz), 7.10 (dd, 2H, J=8.8 Hz, J=8.8 Hz), 6.06 (d, 1H,J=5.5 Hz), 4.68 (dd, 1H, J=5.1 Hz, J=5.1 Hz), 4.43 (s, 2H), 4.31-4.18(m, 4H).

Example 61{(2R,3S,4R,5R)-5-[6-Phenethyl-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-59) Step a:{(3aR,4R,6R,6aR)-6-[6-Phenethyl-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methylacetate

[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (775 mg, 0.00210 mol) andtetrakis(triphenylphosphine)-palladium(0) (120 mg, 0.00010 mol) weredissolved in tetrahydrofuran (20 mL) at room temperature under nitrogen.0.5M Phenethylzinc bromide in tetrahydrofuran (5 mL) was added dropwiseover 5 min. The solution was stirred under nitrogen for 30 min at roomtemperature then heated to 60° C. for 30 min. The reaction was poured onsat NH₄Cl (20 mL). Saturated Na₂EDTA (20 mL) was added and the solutionextracted three times with EtOAc. The pooled organics were washed withsaturated Na₂EDTA, brine, dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash chromatography (DCM/EtOAc 10% to 50%)to obtain the product as an oil (643 mg, 70%).

LCMS: R.t. 1.66, ES+ 439.6 (formic acid).

Step b:{(3aR,4R,6R,6aR)-6-[6-Phenethyl-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methanol

{(3aR,4R,6R,6aR)-6-[6-Phenethyl-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methylacetate (643 mg, 0.00147 mol) was treated with 7M ammonia in methanol(10 mL) at room temperature for 1 h. The solution was concentrated andthe residue purified by flash chromatography (DCM/EtOAc 10% to 50%) togive the product as an oil (473 mg, 81%).

LCMS: R.t. 1.52, ES+ 397 (formic acid).

Step c:{(3aR,4R,6R,6aR)-6-[6-Phenethyl-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methylsulfamate

{(3aR,4R,6R,6aR)-6-[6-Phenethyl-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methanol(464 mg, 0.00117 mol) and triethylamine (489 μL, 0.00351 mol) weredissolved in dry N,N-dimethylformamide (10 mL) under nitrogen and thesolution cooled in an ice/water bath. A 2M solution of chlorosulfonamidein acetonitrile previously prepared (800 μL) was added dropwise and thereaction stirred under nitrogen at 0-5° C. After 30 min, 2Mchlorosulfonamide in acetonitrile (800 μL) was added. After 2h, thereaction was quenched with methanol and concentrated. The residue waspurified by flash chromatography (DCM/EtOAc 10% to 60%) to yield theproduct as an oil (435 mg, 78%).

LCMS: R.t. 1.52, ES+ 476.5 (formic acid).

Step d:{(2R,3S,4R,5R)-5-[6-Phenethyl-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-59)

{(3aR,4R,6R,6aR)-6-[6-phenethyl-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methylsulfamate (435 mg, 0.000915 mol) was treated with trifluoroaceticacid/water 9:1 (5 mL) for 20 min. The solution was concentrated todryness and the residue purified by HPLC to give the product as alyophilized powder (240 mg, 60%).

LCMS: R.t. 1.22, ES+ 436 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.87 (s, 1H), 8.68 (s, 1H), 7.61 (s, 2H),7.26 (m, 4H), 7.17 (m, 1H), 6.06 (d, 1H, J=5.2 Hz), 5.70 (m, 1H), 5.52(m, 1H), 4.68 (m, 1H), 4.32-4.18 (m, 4H), 3.41 (m, 2H), 3.18 (m, 2H).

Example 62{(2R,3S,4R,5R)-5-[6-(Benzoylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methylsulfamate (I-12) Step a:N-{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-6-yl}benzamide

(−)-Adenosine (0.668 g, 2.5 mmol) was dried by co-evaporation withpyridine three times and dissolved in dry pyridine (12.5 mL).Trimethylsilyl chloride (1.90 mL, 12.5 mmol) was added and the solutionstirred for 15 minutes before adding benzoyl chloride (1.45 mL, 12.5mmol). The reaction mixture was stirred at room temperature for anadditional 2 hours. The mixture was cooled to 0° C. and stirred togetherwith 2.7 mL of water for 5 minutes. Aqueous NH₃ (5.05 mL of 29%) wasadded and the mixture was stirred at room temperature for 30 minutes andevaporated to near dryness. The residue was dissolved in 39 mL of waterand washed with 13 mL of EtOAc. The product precipitated from theaqueous layer and was isolated by filtration to give 0.643 g 69% yield.

LCMS: R.t. 1.09 min, ES+ 372.5 (formic acid).

Step b:N-[9-((3aR,4R,6R,6aR)-6-Hydroxymethyl-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-benzamide

N-{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl}-9H-purin-6-yl]benzamide(0.643 g, 1.73 mmol), 2,2-dimethoxypropane (1.06 mL, 8.66 mmol), andpara-toluenesulfonic acid monohydrate (0.333 g, 1.73 mmol) weredissolved in acetone (43 mL). The solution was stirred at roomtemperature overnight and then heated to 40° C. for 3 hours. Once cooledto room temperature, saturated sodium bicarbonate solution was added tothe reaction mixture and then approximately half the solvent was removedin vacuo. The resulting solution was diluted with water and extractedfour times with CH₂Cl₂. Combined organics were washed with brine anddried over Na₂SO₄. The crude material was purified by silica gelchromatography (0 to 5% MeOH/CH₂Cl₂) to isolate the title compound(0.419 g, 59%)

LCMS: R.t. 1.47 min, ES+ 412.6 (formic acid).

Step c:{(3aR,4R,6R,6aR)-6-[6-(Benzoylamino)-9H-purin-9-yl]-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl}methylsulfamate

A solution ofN-[9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl]benzamide(0.419 g, 1.02 mmol) and TEA (0.284 mL, 2.04 mmol) in 3.4 mL of dry DMFwas cooled with an ice bath. A 1M solution of chlorosulfonamide (1.53mL) in acetonitrile was added slowly. The resulting cloudy solution wasstirred while warming to room temperature for approximately 6 hours. Thereaction mixture was concentrated and the residue was dissolved inCH₂Cl₂ and washed with water. The aqueous layer was extracted threetimes with CH₂Cl₂. The combined organics were washed with brine anddried over Na₂SO₄. The crude product was purified by silica gelchromatography (1% to 5% MeOH/CH₂Cl₂) to collect the title compound as awhite solid (0.315 g, 63%)

LCMS: R.t. 1.57 min, ES+ 491.6 (formic acid).

Step d:{(2R,3S,4R,5R)-5-[6-(Benzoylamino)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-furan-2-yl}methylsulfamate (I-12)

Approximately 3 mL of 90% TFA/H₂O was added to{(3aR,4R,6R,6aR)-6-[6-(benzoylamino)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylsulfamate (0.315 g, 0.642 mmol) and stirred together for 20 minutes atroom temperature. The solvent was removed and the product was purifiedby HPLC (0.113 g, 39%).

LCMS: R.t. 1.20 min, ES+ 451.5 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ11.18 (s, 1H); 8.76 (s, 1H); 8.63 (s, 1H);8.06 (d, J=7.162 Hz, 2H); 7.67-7.63 (m, 1H); 7.60-7.52 (m, 4H); 6.08 (d,J=5.41 Hz, 1H); 4.70 (t, J=5.26 Hz, 1H); 4.33-4.19 (m, 4H).

Example 63((3aR,4R,6R,6aR)-6-{6-[(4-Fluorobenzoyl)amino]-9H-purin-9-yl}-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (I-47)

The product was prepared as described in Example 62, steps a-d, using4-fluorobenzoyl chloride in step a.

LCMS: R.t. 1.12 min, ES+ 469 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.76 (s, 1H), 8.63 (s, 1H); 8.12 (m, 1H);7.61 (br, 2H); 7.39 (t, J=9.0, 8.8 Hz, 2H); 6.09 (d, J=5.3 Hz, 1H); 5.71(d, J=5.8 Hz, 1H); 5.49 (d, J=5.02 Hz, 1H); 4.70 (q, J=5.3, 5.5 Hz, 1H);4.33-4.19 (m, 4H).

Example 64((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(phenylsulfonyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methylsulfamate (I-48) Step a:[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl]methylacetate

[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methanol(0.500 g, 1.63 mmol) was dissolved in pyridine (12.5 mL) and cooled withan ice bath. Acetic anhydride (0.154 mL, 1.63 mmol) was added slowly andthe reaction was warmed to room temperature then stirred overnight. Thereaction mixture was then poured over ice and extracted three times withCH₂Cl₂. Combined organics were washed with CuSO₄ (aq) solution, driedover Na₂SO₄, and concentrated. The crude material was purified by flashchromatography (70% to 100% EtOAc/Hex) to afford product 0.336 g (59%).

LCMS: R.t. 1.41 min, ES+ 350.5 (formic acid).

Step b:(3aR,4R,6R,6aR)-6-(6-Benzenesulfonylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl acetate

-   [(3aR,4R,6R,6aR)-6-(6-Amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methyl    acetate (0.738 g, 2.11 mmol) and benzene sulfonyl chloride (0.942    mL, 7.39 mmol) were dissolved in dry pyridine (21 mL) and stirred at    80° C. After 22 hours, extra benzenesulfonyl chloride (0.942 mL,    7.39 mmol) was added and the reaction mixture was stirred at 80° C.    for 6 additional hours. The solvent was then removed in vacuo, and    the residue was dissolved in CH₂Cl₂. The organics were washed with    water, then brine, dried over Na₂SO₄, and concentrated. The dark    orange crude oil was purified by flash column chromatography (70% to    100% EtOAc/Hex) to obtain product (0.600 g, 58%).

LCMS: R.t. 1.66 min, ES+ 490.5 (formic acid).

Step c:N-{9-[(3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}benzenesulfonamide

(3aR,4R,6R,6aR)-6-(6-Benzenesulfonylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylacetate (0.600 g, 1.23 mmol) was dissolved in approximately 3 mL of 7NNH₃/MeOH solution and stirred at room temperature overnight. Thereaction mixture was then concentrated in vacuo and the crude productwas purified by flash chromatography (0% to 5% MeOH/CH₂Cl₂) to afford awhite solid (0.330 g, 60%).

LCMS: R.t. 1.34 min, ES+ 448 (formic acid).

Step d:((3aR,4R,6R,6aR)-2,2-Dimethyl-6-{6-[(phenylsulfonyl)amino]-9H-purin-9-yl}-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate

N-{9-[(3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}benzenesulfonamide(0.293 g, 0.655 mmol) was treated with chlorosulfonamide as described inExample 62, step c, with a reaction time of 2 hours. The crude productwas purified by silica gel chromatography (0% to 1% MeOH/EtOAc) to givea foam (0.142 g, 41%).

LCMS: R.t. 1.55 min, ES+ 527.5 (formic acid).

Step e:((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(phenylsulfonyl)amino]-9H-purin-9-yl}-tetrahydrofuran-2-yl)methylsulfamate (I-48)

Approximately 3 mL of 90% TFA/H₂O was added to((3aR,4R,6R,6aR)-2,2-dimethyl-6-{6-[(phenylsulfonyl)amino]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (0.142 g, 0.270 mmol) and the mixture was stirred for 30minutes at room temperature. The solvent was removed and the product waspurified by HPLC (0.0727 g, 55%).

LCMS: R.t. 1.25 min, ES+ 487.5 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ12.93 (bs, 1H); 8.46 (bs, 1H); 8.37 (s, 1H);7.98 (bs, 2H); 7.62-7.54 (m, 5H); 5.96 (d, J=5.3, 2H); 5.66, (d, J=5.5,1H); 5.45 (d, J=5.3, 1H); 4.56 (m, 1H); 4.29-4.15 (m, 3H).

Example 65((2R,3S,4R,5R)-5-{2-Amino-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-18)

The title compound was prepared following the procedure described inExample 1 using 2-amino-6-chloropurine riboside as starting material and(S)-(+)-1-aminoindane in step b.

LCMS: R.t. 1.31 min, ES+ 478 (ammonium acetate).

¹H-NMR (300 MHz, CD₃OD): δ 8.00 (s, 1H), 7.33 (m, 4H), 6.00 (d, 1H,J=5.4 Hz), 5.93 (br, 1H), 4.76 (t, 1H, J=5.3 Hz), 4.49 (ddd, 2H, J=3.7Hz, J=10.0 Hz, J=11.0 Hz), 4.47 (m, 1H), 4.38 (dd, 1H, J=3.8 Hz, J=7.5Hz), 3.16 (ddd, 1H, J=3.4 Hz, J=8.7 Hz, J=15.9 Hz), 2.99 (td, 1H, J=6.0Hz, J=19.8 Hz), 2.74 (dtd, 1H, J=4.0 Hz, J=7.8 Hz, J=15.8 Hz), 2.06 (tt,1H, J=5.7 Hz, J=15.8 Hz)

Example 66((1R,2R,3S,4R)-4-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,3-dihydroxycyclopentyl)methylsulfamate (I-29) Step a:(1R,2S,3R,5R)-3-[(5-Amino-6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)-cyclopentane-1,2-diol

(1R,2S,3R,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-1-aminocyclopentanehydrochloride (250.0 mg, 0.001361 mol) and5-amino-4,6-dichloropyrimidine (240.0 mg, 0.001463 mol) andTriethylamine (395.0 μL, 0.002834 mol) in 1-Butanol (4.0 mL, 0.044 mol)were reacted in a microwave at 180° C. for 20 minutes. The reaction wasconcentrated in vacuo to dryness, redissolved in EtOH and pre-adsorbedonto silica. This was then eluted through a silica plug with EtOAc torecover starting pyrimidine. Elution with 20% EtOH/EtOAc gave product(285 mg, 76%).

LCMS: R.t. 0.96 min, ES+ 275 (ammonium acetate).

Step b:[(3aR,4R,6R,6aS)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

(1R,2S,3R,5R)-3-[(5-Amino-6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol(335.0 mg, 0.001219 mol) and p-toluenesulfonic acid monohydrate (280 mg,0.0015 mol) was dissolved in N,N-dimethylformamide (5.00 mL) andtrimethoxymethane (10.0 mL, 0.0914 mol) under an atmosphere of nitrogenat 25° C. The reaction was stirred overnight, concentrated in vacuo,diluted with water and concentrated in vacuo again. The residue was thentwice concentrated in vacuo from toluene. The residue was taken up inacetone (15.0 mL, 0.204 mol) and 2,2-dimethoxypropane (5.0 mL, 0.041mol) and stirred for 2 hours, until complete by LCMS. The mixture wasbasified with sodium bicarbonate solution (20 mL), and concentrated invacuo to remove organic solvent. The aqueous residue was extracted withDCM (4×20 mL) and the combined organic phase was concentrated in vacuo.Flash chromatography (0-100% EtOAc/DCM) gave the desired product (210mg, 53%)

LCMS: R.t. 1.65 min, ES+ 325 (ammonium acetate).

Step c:((3aR,4R,6R,6aS)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

[(3aR,4R,6R,6aS)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(210.0 mg, 0.0006466 mol) and (S)-(+)-1-aminoindane (103.7 μL, 0.0008083mol) was dissolved in ethanol (3.0 mL, 0.051 mol) and triethylamine(135.2 μL, 0.0009699 mol). The reaction was microwaved at 150° C. for 11minutes. The reaction was concentrated in vacuo and the residue purifiedby flash chromatography (0 to 100% EtOAc/methylene chloride) to yieldthe product (175 mg, 64%)

LCMS: R.t. 2.17 min, ES+ 422 (ammonium acetate).

Step d:((3aR,4R,6R,6aS)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[r][1,3]dioxol-4-yl)methylsulfamate

6-[6-(Indan-1-ylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]-dioxol-4-yl-methanol(170.0 mg, 0.0004033 mol) was dissolved in methylene chloride (4 mL,0.06 mol) and triethylamine (85 μL, 0.00061 mol) under an atmosphere ofnitrogen. The reaction was cooled on an ice bath. 2.0 M ofchlorosulfonamide in acetonitrile (0.30 mL, 0.00060 mol) was added andthe mixture was stirred for 90 minutes at 0° C. The reaction wasquenched with diluted sodium bicarbonate solution (20 mL) and extractedwith DCM (3×20 mL). The organics were evaporated, taken up in EtOAc andfiltered through a pad of silica, eluting with EtOAc. The filtrates wereconcentrated and dried under vacuum to yield the product (160 mg, 79%)

LCMS: R.t. 1.59 min, ES+ 501 (ammonium acetate).

Step e:((1R,2R,3S,4R)-4-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,3-dihydroxycyclopentyl)methylsulfamate (I-29)

((3aR,4R,6R,6aS)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methylsulfamate (160 mg, 0.00032 mol) was dissolved in TFA/H₂O 9:1 (10.0 mL)and was stirred for 10 minutes The reaction was concentrated in vacuo todryness and concentrated in vacuo twice from MeOH. The crude residue waspurified by reverse phase HPLC to give the product (65 mg, 44%)

LCMS: R.t. 1.24 min, ES+ 461 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 7.73 (s, 1H), 7.57 (s, 1H), 6.66 (m, 4H),5.31 (br, 1H), 3.96 (dd, 1H, J=5.6 Hz, J=8.6 Hz), 3.72 (dq, 2H, J=5.8Hz, J=9.9 Hz), 3.53 (dd, 1H, J=3.3 Hz, J=5.5 Hz), 2.78 (m, 2H), 2.51(ddd, 1H, J=3.6 Hz, J=8.6 Hz, J=15.8 Hz), 2.37 (td, 1H, J=8.1 Hz, J=15.9Hz), 2.11 (dtd, 1H, J=3.7 Hz, J=7.7 Hz, J=12.6 Hz), 1.93 (m, 2H), 1.44(m, 2H)

Example 67[(2R,3S,4R,5R)-3,4-Dihydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydro-furan-2-yl]methylsulfamate (I-5) Step a:[(3aR,4R,6R,6aR)-6-(6-Amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate

[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methanol(4.071 g, 0.01325 mol) was dissolved in pyridine (50 mL, 0.6 mol) andacetic anhydride (1500 μL, 0.016 mol) was added. The solution wasstirred at room temperature for 15 h, and more acetic anhydride (250 μL)was added. After 5h, ethanol (10 mL) was added and the solution stirredfor 10 min then concentrated in vacuo. The residue was taken up inchloroform and the solution washed twice with saturated NaHCO₃ thentwice with saturated CuSO₄, dried over Na₂SO₄ and concentrated in vacuoto dryness. The residue was purified by flash chromatography (DCM/MeOH1% to 4%) to obtain the product as an oil (3.774 g, 82%). LCMS: R.t.1.03 min, ES+ 350 (formic acid).

Step b:[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate

[(3aR,4R,6R,6aR)-6-(6-Amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (3.77 g, 0.0108 mol) was dissolved in dibromomethane (150 mL,2.2 mol) and cooled in an ice/water bath under nitrogen. tert-Butylnitrite (25.7 mL, 0.216 mol) and then bromotrimethylsilane (4.28 mL,0.0324 mol) were added dropwise. After 6h, the reaction was addeddropwise to cooled saturated NaHCO₃/DCM 1:1 (500 mL). The organic waswashed with water then brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography (DCM/EtOAc 20%to 40%) to obtain the product as a white solid (3.79 g, 85%).

LCMS: R.t. 1.44 min, ES+ 415 (formic acid).

Step c:{(3aR,4R,6R,6aR)-2,2-Dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydro-furo[3,4-d][1,3]-dioxol-4-yl}methylacetate

[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (749 mg, 0.00181 mol), copper(I) iodide (69.0 mg, 0.000362 mol)and bis(triphenylphosphine)palladium(II) chloride (127 mg, 0.000181 mol)were dissolved in dry N,N-dimethylformamide (37 mL, 0.48 mol) undernitrogen. Dry N,N-diisopropylethylamine (631 μL, 0.00362 mol) thenphenylacetylene (798 μL, 0.00725 mol) were added. The yellow solutionwas heated at 75° C. for 1 h then concentrated in vacuo. The residue wastaken in DCM and the solution washed three times with saturated Na₂EDTA,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (hexane/EtOAc 20% to 60%) to obtain compound as afoam (659 mg, 84%) which was used without further purification.

LCMS: R.t. 1.76 min, ES+ 435 (formic acid).

Step d:{(3aR,4R,6R,6aR)-2,2-Dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydro-furo[3,4-d][1,3]dioxol-4-yl}methanol

{(3aR,4R,6R,6aR)-2,2-Dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylacetate (650 mg, 0.0015 mol) was treated with 7M ammonia in methanol (10mL) at room temperature for 1 h. The solution was concentrated in vacuoand the residue purified by flash chromatography (DCM/EtOAc 20% to 60%)to obtain the product (465 mg, 79%) as a white solid.

LCMS: R.t. 1.56 min, ES+ 393 (formic acid).

Step e:{(3aR,4R,6R,6aR)-2,2-Dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylsulfamate

{(3aR,4R,6R,6aR)-2,2-Dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methanol(463 mg, 0.00118 mol) and triethylamine (329 μL, 0.00236 mol) weredissolved in dry acetonitrile (10 mL, 0.2 mol) under nitrogen. Thesolution was cooled in an ice bath and 2M chlorosulfonamide inacetonitrile (800 μL) was added dropwise. After 1h, more triethylamine(300 μL) and 2M chlorosulfonamide in acetonitrile (800 μL) were added.After 30 min, the reaction was quenched with MeOH concentrated in vacuoand the residue was purified by flash chromatography (DCM/EtOAc 10% to40%) to obtain the product as a white solid (378 mg, 68%).

LCMS: R.t. 1.62 min, ES+ 472 (formic acid).

Step f:{(2R,3S,4R,5R)-3,4-Dihydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydro-furan-2-yl}methylsulfamate (I-5)

{(3aR,4R,6R,6aR)-2,2-Dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylsulfamate (370 mg, 0.00078 mol) was treated with trifluoroaceticacid/water 9:1 (5 mL) for 30 min. The solution was concentrated in vacuoand the residue taken in methanol to obtain the product as a white solid(234 mg, 69%) which was isolated by filtration.

LCMS: R.t. 1.26 min, ES+ 432 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): S 8.95 (s, 1H), 8.78 (s, 1H), 7.72 (m, 2H),7.62 (s, 2H), 7.54 (m, 3H), 6.08 (d, 1H, J=4.9 Hz), 4.68 (dd, 1H, J=4.8Hz, J=4.8 Hz), 4.35-4.20 (m, 4H).

Example 68((2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methylsulfamate (I-60) Step a:(2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydrofuran-3,4-diol

To a solution of 6-chloro-9-β-D-ribofuranosylpurine (5.00 g, 17.4 mmol)and triphenylmethyl chloride (9.72 g, 34.8 mmol) in DMF (60 mL) wasadded DIPEA (2.7 mL, 19.1 mmol) dropwise. The reaction was heated to 40°C. overnight, cooled to r.t. and filtered. The yellow filtrate wasdiluted with chloroform and washed with water, 0.5 N HCl, and water. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The yellowfoam was purified by flash chromatography (0 to 4% MeOH/CHCl₃) to yieldthe product as a pale yellow foam (5.99 g, 65%).

LCMS: R.t. 1.93 min ES+ 529, 531 (formic acid).

Step b:(2R,3S,4R,5R)-5-(6-Chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]-tetrahydrofuran-3-ylbenzoate

To a solution of(2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydrofuran-3,4-diol(5.99 g, 11.3 mmol) in pyridine (20 mL) at 0° C. was added benzoylchloride (1.45 mL, 12.5 mmol) dropwise. After stirring for six hours theyellow solution was diluted with methylene chloride, washed withsaturated aq sodium bicarbonate (3×), saturated aq copper sulfate (3×)and water (4×). The organic layer was dried (Na₂SO₄), filtered andconcentrated. The brown foam was purified by flash chromatography (0 to1% MeOH/CHCl₃) to give a mixture of regioisomers. The mixture wasre-purified in 1 g batches by flash chromatography (0 to 2% MeOH/CHCl₃)to yield the product as a white solid (1.505 g, 21%).

LCMS: R.t. 2.29 min ES+ 633, 635 (formic acid).

Step c:(2R,3R,4S,5R)-5-(6-Chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydrofuran-3-ylbenzoate

To a solution of(2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydrofuran-3-ylbenzoate (0.905 g, 1.43 mmol) and pyridine (0.7 mL, 8.58 mmol) in DCM(40 mL) at 0° C. was added diethylaminosulfur trifluoride (0.75 mL, 5.72mmol) dropwise. The reaction was stirred at 0° C. for one hour, warmedto r.t., and heated at reflux overnight. The reaction was cooled tor.t., quenched with 5% aq sodium bicarbonate and diluted with DCM. Theorganic layer was washed with saturated aq copper sulfate (2×), water(4×), dried (MgSO₄), filtered, and concentrated. The yellow oil waspurified by flash chromatography (0 to 2% MeOH/CHCl₃) to yield theproduct as a yellow foam (0.781 g, 86%).

LCMS: R.t. 2.42 min ES+ 635, 637 (formic acid).

Step d:(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluoro-2-[(trityloxy)methyl]tetrahydrofuran-3-ylbenzoate

A solution of(2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydrofuran-3-ylbenzoate (0.781 g, 1.23 mmol), (S)-(+)-1-aminoindan (0.316 mL, 2.46mmol) and Et₃N (0.343 mL, 2.46 mmol) in ethanol (25 mL) was heated atreflux overnight. The brown mixture was cooled to r.t. and concentrated.The residue was purified by flash chromatography (0 to 2% MeOH/CHCl₃) toyield the product (0.705 g, 79%).

LCMS: R.t. 2.57 min ES+ 732 (formic acid).

Step e:(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ylbenzoate

To a solution of(2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluoro-2-[(trityloxy)methyl]tetrahydrofuran-3-ylbenzoate (0.715 g, 0.98 mmol) in ether (9 mL) was added formic acid (6mL) and the reaction was stirred for four hours. The solution wasdiluted with ether and washed with saturated aq sodium bicarbonate toquench. The organic layer was dried (Na₂SO₄), filtered and concentrated.The beige foam was purified by flash chromatography (0 to 2% MeOH/CHCl₃)to yield the product (0.468 g, 98%).

LCMS: R.t. 1.87 min ES+ 490 (formic acid).

Step f:(2R,3R,4S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluorotetrahydrofuran-3-ylbenzoate

The title compound was prepared following the procedure described inExample 67 step e using DMF as the solvent.

LCMS: R.t. 1.83 min ES+ 569 (formic acid).

Step g:((2R,3R,4S,5R)-5-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methylsulfamate (I-60)

The title compound was prepared following the procedure described inExample 67 step d using(2R,3R,4S,5R)-2-{[(aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-4-fluorotetrahydrofuran-3-ylbenzoate.

LCMS: R.t. 1.46 min ES+ 465 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.34 (bs, 1H); 8.22 (d, J=2.4 Hz, 1H);7.36-7.12 (m, 4H); 6.56 (dd, J=3.7 Hz, 17.9 Hz, 1H); 5.90 (bs, 1H);5.25-5.08 (dt, J=3.1 Hz, 51.7 Hz, 1H); 4.57 (dt, J=3.2 Hz, 16.5 Hz, 1H);4.40 (d, J=5.1 Hz, 2H); 4.26 (q, J=4.5 Hz, 1H); 3.17-3.03 (m, 1H);3.02-2.63 (m, 1H); 2.75-2.63 (m, 1H); 2.11-1.98 (m, 1H).

Example 69{(2R,3S,4R,5R)-5-[6-(2-furyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-94) Step a:{(3aR,4R,6R,6aR)-6-[6-(2-furyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methylacetate

[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methylacetate (0.10 g, 0.242 mmol), 2-(tributylstannyl)furan (0.08 mL, 0.242mmol) and bis(triphenylphosphine)palladium(II) chloride (0.008 g, 0.012mmol) were stirred in DMF (1 mL) under an atmosphere of argon for 4hours. The mixture was filtered through a pad of Celite and thenconcentrated. The residue was purified by preparative platechromatography (50% EtOAc/hexanes) to give the title compound as ayellow foam (0.076 g, 78%).

LCMS: R.t. 2.45 min ES+ 401 (formic acid).

Step b:{(2R,3S,4R,5R)-5-[6-(2-furyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-methylsulfamate (I-94)

The title compound was prepared following the procedure described inExample 67, steps d-f using DCM as the solvent in step e.

LCMS: R.t. 1.02 min ES+ 398 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.91 (s, 1H); 8.77 (s, 1H), 8.08 (bs, 1H);7.85 (d, J=3.4 Hz, 1H); 7.50 (bs, 1H); 6.85-6.79 (m, 1H); 6.09 (d, J=5.1Hz, 1H); 5.74 (bs, 1H); 5.54 (bs, 1H); 4.69 (bs, 1H); 4.37-4.16 (m, 4H).

Example 70((2R,3S,4R,5R)-5-{6-[(2-Chlorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-71)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-chloro-2-ethynyl-benzene in step c and DCMas the solvent in step e.

LCMS: R.t. 1.42 min ES+ 466 (formic acid

¹H-NMR (300 MHz, CD₃OD): δ 8.92 (s, 1H); 8.73 (s, 1H); 7.84 (d, J=7.6Hz, 1H); 7.58-7.33 (m, 3H); 6.21 (d, J=4.9 Hz, 1H); 4.76 (t, J=4.9 Hz,1H); 4.48-4.29 (m, 4H).

Example 71((2R,3S,4R,5R)-5-{6-[(3-Fluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-88)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-fluoro-3-ethynyl-benzene in step c and DCMas the solvent in step e.

LCMS: R.t. 1.35 min ES+ 450 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.92 (s, 1H); 8.76 (s, 1H); 7.63-7.42 (m,3H); 7.25 (dt, J=2.4 Hz, J=10.5 Hz, 1H); 6.20 (d, J=4.8 Hz, 1H); 4.76(t, J=4.9 Hz, 1H); 4.47-4.27 (m, 4H).

Example 72((2R,3S,4R,5R)-3,4-Dihydroxy-5-{6-[(2-methoxyphenyl)ethynyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methylsulfamate (I-90)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-ethynyl-2-methoxy benzene in step c andDCM as the solvent in step e.

LCMS: R.t. 1.23 min ES+ 462 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): S 8.95 (s, 1H); 8.80 (s, 1H); 7.66-7.45 (m,4H); 7.17 (d, J=8.4 Hz, 1H): 7.06 (t, J=7.4 Hz, 1H); 6.09 (d, J=5.0 Hz,1H); 5.70 (s, 1H); 5.49 (s, 1H); 4.68 (s, 1H); 4.38-4.14 (m, 1H); 3.91(s, 3H)

Example 73((2R,3S,4R,5R)-5-{6-[(4-Bromophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-150)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-bromo-4-ethynylbenzene in step c and DCMas the solvent in step e.

LCMS: R.t. 1.49 min ES+ 509, 511 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 8.93 (s, 1H); 8.73 (s, 1H); 7.81-7.57 (m,4H); 6.06 (d, J=5.0 Hz, 1H); 4.67 (t, J=4.9 Hz, 1H); 4.36-4.15 (m, 4H).

Example 74[(2R,3S,4R,5R)-3,4-Dihydroxy-5-(6-{[3-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-108)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-ethynyl-3-(trifluoromethyl)benzene in stepc and DCM as the solvent in step e.

LCMS: R.t. 1.52 min ES+ 501 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 9.00 (s, 1H); 8.85 (s, 1H); 8.08-8.01 (m,2H); 7.92 (d, J=7.9 Hz, 1H); 7.78 (t, J=7.7 Hz, 1H); 7.60 (s, 2H); 6.10(d, J=5.1 Hz, 1H); 5.72 (d, J=5.7 Hz, 1H); 5.50 (d, J=5.4 Hz, 1H); 4.69(q, J=5.3 Hz, 1H); 4.37-4.15 (m, 4H).

Example 75((2R,3S,4R,5R)-5-{6-[(4-Fluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-144)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-ethynyl-4-fluorobenzene in step c and DCMas the solvent in step e.

LCMS: R.t. 1.34 min ES+ 450 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.96 (s, 1H); 8.82 (s, 1H); 7.79 (t, J=5.4Hz, 2H); 7.61 (bs, 2H); 7.37 (t, J=8.9 Hz, 2H); 6.09 (d, J=5.0 Hz, 1H);4.69 (t, J=4.9 Hz, 1H); 4.37-4.17 (m, 4H).

Example 76((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate Step a:(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol

To a solution of (1S,5S)-5-(hydroxymethyl)cyclopent-2-en-1-ol (3.19 g,27.9 mmol) (An, G.-I.; Rhee, H. Nucleosides Nucleotides 2002, 21, 65-72)in DCM (143 mL) at 0° C. was added 3-chloroperbenzoic acid (7.52 g, 33.5mmol) and the mixture was stirred at room temperature for 4 hours.Silica gel (20 g) was added, the mixture was concentrated to dryness andwas purified via flash chromatography (0 to 100% EtOAc/DCM) to affordthe title compound (2.75 g, 76%).

LCMS: R.t. 0.37 min ES+ 131 (ammonium acetate).

Step b:(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine

To a solution of(1R,2R,3S,5S)-3-(hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol (3.65 g,21.0 mol) in DCM (121 mL) at 0° C. was added1-(dimethoxymethyl)-4-methoxybenzene (10.7 mL, 63.1 mmol) followed bypyridinium p-toluenesulfonate (530. mg, 2.11 mmol). The mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated and the residue was purified by flash chromatography (0 to50% EtOAc/hexanes) to afford the title compound (4.10 g, 78%).

LCMS: R.t 1.68 min ES+ 249 (ammonium acetate).

Step c:N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol),DIPEA (3.57 mL, 20.5 mmol) and (S)-(+)-1-aminoindan (1.93 mL, 15.0 mmol)in 1-butanol (60.0 mL) and was heated to reflux for 60 hours, cooleddown to room temperature and concentrated. The residue was purified byflash chromatography (0 to 100% EtOAc/DCM) to afford the title compound(2.72 g, 80%).

LCMS: R.t 1.42 min ES+ 251 (ammonium acetate).

Step d:(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol

To a solution ofN-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(3.70 g, 14.8 mmol) in DMF (49.4 mL) under an atmosphere of nitrogen wasadded NaH (60% by weight in mineral oil, 546 mg, 13.6 mmol) and thesuspension was stirred at 70° C. for 10 minutes. To this was added(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine(2.82 g, 11.4 mmol) in DMF (35.3 mL) and the reaction was stirred at110° C. for 2 hours. The reaction mixture was cooled, quenched withbrine (30 mL), extracted with ethyl acetate (3×50 mL), dried (MgSO₄),filtered, and concentrated. The residue was purified by flashchromatography (30 to 100% EtOAc/hexanes) to afford the title compound(3.90 g, 69%).

LCMS: R.t 1.86 min ES+ 500 (ammonium acetate).

Step e:O-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]-dioxin-7-yl]O-phenylthiocarbonate

To a solution of(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol(4.00 g, 8.02 mmol) in DCM (169 mL) under an atmosphere of Ar was addedDMAP (2.94 g, 24.1 mmol) followed by phenyl chlorothionocarbonate (2.22mL, 16.0 mmol). The mixture was stirred at room temperature for 1 hour.The solvent was concentrated and purified by flash chromatography (20 to100% EtOAc/hexanes, column pre-treated with 1% Et₃N/hexanes) to affordthe title compound (5.00 g, 99%).

LCMS: R.t 2.34 min ES+ 636 (ammonium acetate).

Step f:N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution ofO-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenylthiocarbonate (5.00 g, 7.88 mmol) in toluene (150. mL) under anatmosphere of nitrogen was added Bu₃SnH (4.24 mL, 15.8 mmol) followed by2,2′-azo-bis-isobutyronitrile (259 mg, 1.58 mmol). The solution washeated to reflux for 30 minutes, the mixture was cooled, concentrated to30 mL and the residue was purified by flash chromatography (30 to 100%EtOAc/hexanes) to afford the title compound (3.00 g, 79%).

LCMS: R.t 2.12 min ES+ 483 (ammonium acetate).

Step g:(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentanol

A solution ofN-[(1S)-2,3-dihydro-1H-inden-1-yl]-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(3.00 g, 5.90 mmol) in THF (11.6 mL), water (11.6 mL) and AcOH (34.9 mL,614 mmol) was stirred at room temperature under an atmosphere of argonfor 60 hours. The mixture was concentrated and the residue was purifiedvia flash chromatography (0 to 10% MeOH/DCM) to afford the titlecompound (2.10 g, 98%).

LCMS: R.t 1.46 min ES+ 365 (ammonium acetate).

Step h:((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate

The title compound was prepared following the procedure described inExample 40 steps a-b and steps e-g using CH₃CN as the solvent in step f.

LCMS: R.t 1.54 min ES+ 444 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.16 (s, 1H), 7.26-7.12 (m, 5H), 6.63 (d,J=3.6 Hz, 1H), 5.85 (dd, J=7.6, 7.6 Hz, 1H), 5.46-5.40 (m, 1H),4.50-4.47 (m, 1H), 4.37 (d, J=7.6, 9.6 Hz, 1H), 4.19 (dd, J=7.4, 9.6 Hz,1H), 3.08-3.02 (m, 1H), 2.96-2.87 (m, 1H), 2.85-2.75 (m, 1H), 2.67-2.59(m, 1H), 2.37-2.20 (m, 3H), 2.07-1.97 (m, 2H) ppm.

Example 77[(1S,2S,4R)-2-Hydroxy-4-(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methylsulfamate

The title compound was prepared following the procedures described inExample 76 steps a-g using (1R,2S)-2-methoxyindan-1-amine (Maruyama, Y.;Hirabayashi, K.; Hori, K. PCT Int. Appl. WO03037862A1, 2003) in step cand Example 86 steps g-h.

LCMS: R.t. 1.46 min ES+ 474 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.20 (s, 1H), 7.27-7.14 (m, 5H), 6.67 (d,J=3.6 Hz, 1H), 5.90 (d, J=5.2 Hz, 1H), 4.49 (t, J=3.5 Hz, 1H), 4.37 (dd,J=7.6, 9.7 Hz, 1H), 4.31-4.28 (m, 1H), 4.20 (dd, J=7.3, 9.7 Hz, 1H),3.31-3.29 (m, 4H) 3.19-3.05 (m, 2H), 2.85-2.77 (m, 1H), 2.37-2.20 (m,3H), 2.08-2.00 (m, 1H).

Example 78[(1R,2R,3S,4R)-2,3-dihydroxy-4-(6-isobutyl-9H-purin-9-yl)cyclopentyl]methylsulfamate (I-97) Step a:[(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl]methyl acetate

To a solution of((3aR,4R,6R,6aS)-[6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl]-methanol(2.3 g, 6.4 mmol) in DCM (20 mL) and pyridine (1.03 mL, 0.0127 mol) wasadded acetic anhydride (1.20 mL, 12.7 mmol) andN,N-dimethylaminopyridine (20 mg, 0.10 mmol). The reaction was stirredfor 2 hours, diluted with DCM, and washed with water. The organic phasewas concentrated and the residue was purified by flash chromatography (0to 100% EtOAc/hexanes) to yield the product (1.83 g, 78%).

LCMS: R.t. 2.20 min ES+ 367 (formic acid).

Step b:[(3aR,4R,6R,6aS)-6-(6-isobutyl-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methylacetate

To a solution of[(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methylacetate (250.0 mg, 0.68 mmol) in degassed THF (6 mL) under nitrogen wasadded Pd(PPh₃)₄ (44 mg, 0.038 mmol) followed by 0.5 M of isobutylzincbromide in tetrahydrofuran (2.04 mL) dropwise over 15 min. The reactionwas heated at 60° C. for 1 hour. The reaction was cooled then quenchedwith saturated aq NH₄Cl, extracted with EtOAc and the organic phase waswashed with saturated aq EDTA.Na₂ solution then water. The organic phasewas concentrated and the residue purified by flash chromatography (0 to100% EtOAc/DCM) to provide the title compound (120 mg, 45%).

LCMS: R.t. 1.60 min ES+ 389 (formic acid).

Step c:[(1R,2R,3S,4R)-2,3-dihydroxy-4-(6-isobutyl-9H-purin-9-yl)cyclopentyl]methylsulfamate (I-97)

The title compound was prepared following the procedure described inExample 67, steps d-f.

LCMS: R.t. 1.08 min ES+ 386 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): S 8.87 (s, 1H); 8.66 (s, 1H); 7.52 (bs, 2H);4.86 (dd, J=9.3, 18.1 Hz, 1H); 4.41 (dd, J=5.3, 9.0 Hz, 1H); 4.17 (dd,J=6.8, 9.8 Hz, 1H); 4.08 (dd, J=6.3, 9.8 Hz, 1H); 3.88 (dd, J=2.8, 5.2Hz, 1H); 2.98 (d, J=7.2 Hz, 1H); 2.40-2.27 (m, 3H); 1.87-1.78 (m, 1H);0.92 (d, J=6.7 Hz, 6H).

Example 79[(1R,2R,3S,4R)-2,3-dihydroxy-4-(6-propyl-9H-purin-9-yl)cyclopentyl]methylsulfamate (I-96)

The title compound was prepared following the procedure described inExample 78, steps b-c using n-propylzincbromide in step b.

LCMS: R.t. 0.98 min ES+ 372 (formic acid).

¹H-NMR (300 MHz, do-DMSO): δ 8.85 (s, 1H); 8.66 (s, 1H); 7.52 (bs, 2H);4.86 (dd, J=9.3, 18.1 Hz, 1H); 4.41 (dd, J=5.3, 9.0 Hz, 1H); 4.17 (dd,J=6.8, 9.8 Hz, 1H); 4.08 (dd, J=6.3, 9.8 Hz, 1H); 3.88 (dd, J=2.7, 5.2Hz, 1H); 3.09-3.05 (m, 2H); 2.40-2.25 (m, 2H); 1.90.1.79 (m, 3H); 0.93(t, J=7.4 Hz, 3H).

Example 80{(1R,2R,3S,4R)-2,3-dihydroxy-4-[6-(2-phenylethyl)-9H-purin-9-yl]-cyclopentyl}methylsulfamate (I-79)

The title compound was prepared following the procedure described inExample 78, steps b-c using phenethylzincbromide in step b.

LCMS: R.t. 1.26 min ES+ 434 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.85 (s, 1H); 8.65 (s, 1H); 7.52 (bs, 2H);7.30-7.24 (m, 4H); 7.19-7.13 (m, 1H); 4.86 (dd, J=9.3, 18.0 Hz, 1H);4.41 (dd, J=5.3, 9.0 Hz, 1H); 4.17 (dd, J=6.8, 9.8 Hz, 1H); 4.08 (dd,J=6.3, 9.8 Hz, 1H); 3.88 (dd, J=2.7, 5.2 Hz, 1H); 3.40 (dd, J=6.5, 9.3Hz, 2H); 3.17 (dd, J=6.6, 9.3 Hz, 2H); 2.40-2.26 (m, 2H); 1.88-1.78 (m,1H).

Example 81{(1R,2R,3S,4R)-2,3-dihydroxy-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentyl}methylsulfamate (I-138) Step a:[(3aR,4R,6R,6aS)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methylacetate

To a solution of[(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methylacetate (185 mg, 0.45 mmol) in 2-butanone (8 mL) at 0° C. was added NaI(1.36 g, 9.08 mmol) followed by trifluoroacetic acid (174.8 μL, 2.27mmol). The reaction was stirred for 3 hours at 0° C., quenched withsaturated aq NaHCO₃ and extracted with DCM. The organic phase wasconcentrated and the residue was purified by flash chromatography (0 to100% EtOAc/DCM) to obtain the title compound (140 mg, 67%).

LCMS: R.t. 151 min ES+ 459 (formic acid).

Step b:{(3aR,4R,6R,6aS)-2,2-dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

A solution of[(3aR,4R,6R,6aS)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methylacetate (140.0 mg, 0.31 mmol), Pd(PPb₃)₂Cl₂ (25 mg, 0.036 mmol), DIPEA(140 μL, 0.80 mmol), CuI (20 mg, 0.1 mmol) and phenylacetylene (170 μL,1.5 mmol) in DMF (5.0 mL) under an atmosphere of nitrogen was stirred atroom temperature for 20 minutes. The reaction was concentrated and theresidue taken up in DCM (50 mL). This was washed with saturated aqEDTA.Na₂ (2×10 mL) then water (10 mL). The organics were concentrated toprovide a black gum. This crude product was dissolved in DCM (5 mL) and7.0 M of ammonia in methanol (5.0 mL) was added. This was stirred atroom temperature for 2 hours. The reaction was concentrated and theresidue was purified by flash chromatography (0 to 100% EtOAc/DCM) toprovide the title compound (75 mg, 63%).

LCMS: R.t. 1.51 min ES+ 391 (formic acid).

Step c:{(1R,2R,3S,4R)-2,3-dihydroxy-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentyl}methylsulfamate (I-138)

The title compound was prepared following the procedure described inExample 67, steps e-f.

LCMS: R.t. 1.30 min ES+ 430 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.87 (bs, 1H); 8.64 (s, 1H); 7.78-7.73 (m,2H); 7.50-7.41 (m, 3H); 4.98 (dd, J=9.3, 17.9 Hz, 1H); 4.61 (dd, J=5.5,8.8 Hz, 1H); 4.27 (dd, J=2.2, 5.7 Hz, 1H); 4.11 (dd, J=2.9, 5.4 Hz, 1H);2.57-2.42 (m, 2H); 2.18-2.06 (m, 1H); 1.27-1.24 (m, 1H).

Example 82N-[((1R,2R,3S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,3-dihydroxycyclopentyl)methyl]sulfamide(I-87) Step a: tert-Butyl(aminosulfonyl){[(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl}carbamate

To a solution of((3aR,4R,6R,6aS)-[6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl]-methanol(Yang, M.; Wei, Y.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993-3996)(250.0 mg, 0.77 mmol), N-Boc-sulfonamide (226.6 mg, 1.16 mmol) andtriphenylphosphine (242.3 mg, 0.92 mol) in EtOAc (8 mL) was addeddiisopropyl azodicarboxylate (227.3 μL, 1.16 mmol) dropwise as asolution in EtOAc (1 mL). The reaction was stirred at r.t. overnight,quenched with water and extracted with EtOAc. The organics wereconcentrated and the residue purified by flash chromatography (0 to 100%EtOAc/DCM) to obtain the product as an inseparable mixture withtriphenylphosphine oxide. The material was carried on as such.

LCMS: R.t. 2.49 min ES+ 503 (formic acid).

Step b:N-[((1R,2R,3S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2,3-dihydroxycyclopentyl)methyl]sulfamide(I-87)

To the mixture obtained in step a was added trifluoroacetic acid in DCM(3 M, 50 mL). The resulting solution was stirred for 30 minutes thenevaporated. This crude material was combined with (S)-(+)-1-aminoindan(197.6 μL, 1.54 mmol) and Et₃N (214.6 μL, 1.54 mmol) and ethanol (5 mL).The mixture was heated to reflux for 4 hours, then cooled andconcentrated. The residue was dissolved in TFA/water (9:1, 5 mL),stirred for 10 minutes, and concentrated. The residue was purified byflash chromatography (0 to 10% MeOH/EtOAc) and prep HPLC to obtain thetitle compound (49 mg, 13% from step a)

LCMS: R.t. 1.26 min ES+ 460 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.21 (bs, 1H); 8.15 (s, 1H); 7.28-7.05 (m,4H); 5.74 (bs, 1H); 4.67 (dd, J=9.1, 18.0 Hz, 1H); 4.34 (dd, J=5.5, 8.7Hz, 1H); 3.83 (dd, J=3.2, 5.2 Hz, 1H); 3.12-2.91 (m, 3H); 2.88-2.75 (m,1H); 2.32 (td, J=8.8, 12.9 Hz, 1H); 2.18-2.06 (m, 1H); 2.02-1.86 (m,1H); 1.70 (dd, J=10.4, 20.9 Hz, 1H).

Example 83((1R,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (I-141) Step a:(1S,2R,4R)-4-{[6-Chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl]amino}-2-(hydroxymethyl)cyclopentanol

A solution of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (0.485g, 3.69 mmol) (Ho, J. Z.; Mohareb, R. M.; Anh, J. H.; Sim, T. B.;Rapoport, H. J. Org. Chem. 2003, 68, 109-114),4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (0.392 g, 1.48 mmol)(Montgomery, J. A.; Hewson, K. J. Med. Chem. 1967, 10, 665-667) andtriethylamine (0.30 mL, 2.22 mmol) in butanol (4 mL) was microwaveirradiated at 150° C. for 450 seconds. The solution was concentrated andpurified by flash chromatography (100% EtOAc) to give the title compound(0.454 g, 85%).

LCMS: R.t. 1.28 min ES+ 360 (formic acid).

Step b:(1S,2R,4R)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)-cyclopentanol

To a solution of(1S,2R,4R)-4-{[6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl]amino}-2-(hydroxymethyl)cyclopentanol(0.454 g, 1.26 mmol) in dioxane (9 mL) was added 1 N aq HCl (1.8 mL) andthe reaction was stirred for 2 days. The reaction was neutralized to pH˜7 with aq NH₄OH then concentrated. The desired product was trituratedwith ethanol to give a white solid (0.339 g, 100%).

LCMS: R.t. 1.16 min ES+ 268 (formic acid).

Step c:((1R,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (I-141)

The title compound was prepared following the procedure described inExample 40, steps a-b and d-g, using (S)-(+)-1-aminoindane in step d.

LCMS: R.t. 1.12 min ES+ 444 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.13 (d, J=2.3 Hz, 1H); 7.24-7.06 (m, 5H);6.58 (t, J=3.6 Hz, 1H); 5.81 (t, J=7.7 Hz, 1H); 5.28 (m, 1H); 4.30-4.16(m, 2H); 3.72-3.58 (m, 1H); 3.06-2.95 (m, 1H); 2.93-2.81 (m, 1H);2.64-2.53 (m, 1H); 2.51-2.06 (m, 4H); 2.03-1.91 (m, 1H); 1.83-1.66 (m,1H).

Example 84((1R,2S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-hydroxycyclopentyl)methylsulfamate (I-127) Step a:(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-ol

To a solution of(1R,2S,3R,5R)-3-(6-chloro-purin-9-yl)-5-hydroxymethyl-cyclopentane-1,2-diol(Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-308)(0.44 g, 1.55 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.461 mL,3.1 mmol) in AcCN (15 mL) was added1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.581 mL, 1.8 mmol). Thereaction mixture was stirred at room temperature for 14 h thenconcentrated. The residue was purified by flash chromatography (0 to 50%EtOAc/hexanes) to afford the title compound (0.545 g, 67%)

LCMS: R.t. 2.80 min ES+ 527 (formic acid)

Step b:O-[(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-yl]O-phenylthiocarbonate

To a solution of(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-ol(0.762 g, 1.44 mmol) and N,N-dimethylaminopyridine (0.529 g, 4.34 mmol)in DCM (20 mL) was added phenyl chlorothionocarbonate (0.440 mL, 3.2mmol) and the solution was stirred for 1 h. The reaction mixture wasconcentrated and the residue purified by flash chromatography (0 to 50%EtOAc/hexanes) to afford the title compound (0.851 g, 88%).

LCMS: R.t. 3.10 min ES+ 663 (formic acid).

Step c:6-chloro-9-[(6aR,8R,9aS)-2,2,4,4tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]-trioxadisilocin-8-yl]-9H-purine

To a solution ofO-[(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-yl]O-phenylthiocarbonate (0.851 g, 1.28 mol) in toluene (20 mL) was addedtri-n-butyltin hydride (0.680 mL, 2.53 mmol) and2,2′-azo-bis-isobutyronitrile (0.075 g, 0.46 mmol). This solution wasrefluxed for 1 h. The reaction mixture was concentrated and purified byflash chromatography (0 to 50% EtOAc/hexanes) to afford the titlecompound (0.14 g, 74%).

LCMS: R.t. 2.92 min ES+ 512 (formic acid).

Step d:(1S,2R,4R)-4-(6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol

To a solution of6-chloro-9-[(6aR,8R,9aS)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine(0.518 g, 1.0 mmol) in THF/pyridine (5.2 mL, 1:1) was added hydrofluoricacid in pyridine (0.381 mL, 15.2 mmol). The reaction was stirred for 14h then quenched with saturated aq NaHCO₃ and concentrated under reducedpressure. The residue was dissolved in 10% solution of MeOH/DCM,filtered, the organic layer was concentrated and the residue purified byflash chromatography (0 to 10% MeOH/DCM to afford the title compound(0.171 g, 63%).

LCMS: R.t. 0.87 min ES+ 269 (formic acid).

Step e:(1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)-cyclopentanol

To a solution of(1S,2R,4R)-4-(6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol(0.496 g, 0.0018 mol) in DMF (10 mL) was added tert-butyldimethylsilylchloride (0.348 g, 0.0023 mol), N,N-dimethylaminopyridine (0.023 g,0.00019 mol) and imidazole (0.276 g, 0.0041 mol). This solution wasstirred for 1 h and then the reaction mixture was quenched with waterand diluted with ethyl acetate. The organic layer was washed with water,concentrated and purified by flash chromatography (0 to 50% EtOAc/DCM)to afford the title compound (0.462 g, 65%).

LCMS: R.t. 1.99 min ES+ 384 (formic acid).

Step f:(1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}cyclopentanol

A solution of(1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol(0.091 g, 0.24 mmol), triethylamine (0.1 mL, 0.72 mmol) and(S)-1-aminoindane (0.0662 g, 0.48 mmol) in ethanol (5 mL) was refluxedat 95° C. for 14 h and then concentrated under reduced pressure. Theresidue was purified by flash chromatography (0 to 60% EtOAc/DCM) toafford the title compound (0.09 g, 80%).

LCMS: R.t. 2.14 min ES+ 480 (formic acid).

Step g:((1R,2S,4R)-4-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-2-hydroxycyclopentyl)methylsulfamate (I-127)

The title compound was prepared following the procedure described inExample 40 steps b and e-g.

LCMS: R.t. 1.33 min ES+ 445 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.30 (s, 1H), 8.17 (s, 1H), 7.29-7.14 (m,4H), 5.94-5.82 (m, 1H), 5.24-5.09 (m, 1H), 4.39-4.21 (m, 3H), 3.12-3.02(m, 1H), 2.98-2.87 (m, 1H), 2.72-2.56 (m, 2H), 2.53-2.35 (m, 2H),2.31-2.22 (m, 1H), 2.07-1.97 (m, 2H).

Example 85{(1R,2S,4R)-2-hydroxy-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentyl}-methylsulfamate (I-109) Step a:(1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentanol

A solution of(1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol(0.1 g, 0.26 mmol), Pd(PPh₃)₂Cl₂ (0.006 g, 0.0089 mmol), CuI (0.004 g,0.02 mmol) and triethylamine (0.145 mL, 1.04 mmol) in DMF (5 mL) washeated at 70° C. under argon for 1 h. Phenylacetylene (0.057 mL, 0.52mmol) was added, the reaction mixture was stirred for 3 h, and thereaction was concentrated. The residue was dissolved in DCM and washedwith saturated aq NaHCO₃ and saturated aq EDTA.Na₂ acid. The organiclayer was dried (Na₂SO₄), concentrated and purified by flashchromatography (0 to 50% EtOAc/DCM) to afford the title compound (0.096g, 82%).

LCMS: R.t. 2.17 min ES+ 449 (formic acid).

Step b:{(1R,2S,4R)-2-hydroxy-4-[6-(phenylethynyl)-9H-purin-9-yl]cyclopentyl}methylsulfamate (I-109)

The title compound was prepared following the procedure described inExample 40 steps b and e-g.

LCMS: R.t. 1.35 min ES+ 414 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.91 (s, 1H), 8.68 (s, 1H), 7.79 (dd, J=7.6,1.8 Hz, 2H), 7.55-7.43 (m, 3H), 5.39-5.26 (m, 1H), 4.38-4.25 (m, 2H),2.72-2.53 (m, 3H), 2.47-2.29 (m, 3H).

Example 86[(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-hydroxytetrahydrofuran-2-yl]methylsulfamate(I-133) Step a: tent-Butyl (chlorosulfonyl)carbamate

Reference: F. Hirayama et al., Biorg. Med. Chem., 2002, 10, 1509-1523.

To a stirred solution of chlorosulfonyl isocyanate (3.20 mL, 36.0 mmol)in benzene (15.0 mL) in a water bath at rt was added tert-butyl alcohol(3.50 mL, 36.2 mmol) dropwise via syringe under an atmosphere ofnitrogen. After 2 h, the mixture was diluted with hexanes (30.0 mL) andthe resulting white precipitate was filtered and washed with hexanes(3×20 mL). The collected solid was dried in a vacuum desiccator underhouse vacuum for 10 min to afford the title compound as a white solid(5.08 g, 65%). The product was stored under nitrogen in a freezer.

LCMS: R.t. 0.94 min (ES+) 215 (ammonium acetate).

Step b: 5-iodo-7H-pryrrolo[2,3-d]pyrimidine

7H-pyrrolo[2,3-d]pyrimidine (2.17 g, 18.2 mmol) (P. Reigan et al.Bioorg. Med. Chem. Lett. 2004, 14, 5247) and N-iodosuccinimide (4.30 g,19.1 mmol) were stirred in acetonitrile (30 mL) under an atmosphere ofargon for 2 hours. The precipitate was collected to give the titlecompound as an orange solid (4.33 g, 94%).

LCMS: R.t. 0.80 min ES+ 246 (formic acid)

Step c: 5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine

5-iodo-7H-pryrrolo[2,3-d]pyrimidine (0.111 g, 0.453 mmol), CuI (0.00431g, 0.0226 mmol), Pd(PPh₃)₂Cl₂ (0.0318 g, 0.0453 mmol), DIPEA (0.158 mL,0.906 mmol) and (trimethylsilyl)acetylene (0.256 mL, 1.81 mmol) werestirred in DMF (5 mL) under an atmosphere of argon for 3 hours. Themixture was diluted with EtOAc and washed with water (3×) and brine(1×), dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (50 to 100% EtOAc/hexanes) to give thetitle compound as a brown solid (0.0458 g, 47%).

LCMS: R.t. 1.51 min ES+ 216 (formic acid).

Step d: 5-ethynyl-7H-pyrrolo[2,3-d]pyrimidine

5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (0.320 g, 1.49mmol) and potassium carbonate (0.513 g, 3.72 mmol) were stirred in MeOH(6 mL) for 18 hours. The mixture was diluted with EtOAc, washed withsaturated ammonium chloride, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to give the title compound as anorange solid (0.185 g, 87%).

LCMS: R.t. 0.70 min (ES+) 144 (formic acid)

Step e: 5-ethyl-7H-pyrrolo[2,3-d]pyrimidine

5-ethynyl-7H-pyrrolo[2,3-d]pyrimidine (0.293 g, 2.05 mmol) and palladiumhydroxide[20 weight percent (dry basis)] on carbon[moist] (0.0644 g,0.0458 mmol) were stirred in ethanol (10 mL) under an atmosphere ofhydrogen for 18 hours. The mixture was filtered through a pad of celiteand concentrated to give the title compound as an orange solid (0.260 g,86%).

LCMS: R.t. 0.35 min (ES+) 148 (formic acid).

Step f:(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)-tetrahydrofuran-3-ol

The title compound was prepared following the procedure described inExample 91, steps a-b using 5-ethynyl-7H-pyrrolo[2,3-d]pyrimidine.

LCMS: R.t. 0.62 min (ES+) 264 (formic acid).

Step g:tert-butyl({[(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxytetrahydrofuran-2-yl]methoxy}sulfonyl)carbamate

To a solution of(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol(0.0560 g, 0.213 mmol) and 2,6-di-tert-butyl-4-methylpyridine in AcCN (4mL) at 0° C. was added tert-butyl(chlorosulfonyl)carbamate (0.0573 g,0.266 mmol), the solution was warmed to room temperature and stirred for1 hour. The reaction was quenched with 7N ammonia in methanol (2 mL) andconcentrated. The residue was purified by flash chromatography (0 to 10%MeOH/DCM) to give the title compound as a white solid (39 mg, 29%).

LCMS: R.t. 1.20 min (ES+) 443 (formic acid standard).

Step h:[(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-3-hydroxytetrahydrofuran-2-yl]methylsulfamate(I-133)

A solution oftert-butyl({[(2R,3S,5R)-5-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxytetrahydrofuran-2-yl]methoxy}sulfonyl)carbamate(39 mg, 0.617 mmol) in DCM (4 mL) and trifluoroacetic acid (1 mL) wasstirred for 30 minutes. The reaction was concentrated to a yellowresidue. The residue was purified by flash chromatography (0 to 10%MeOH/DCM) to give the title compound as a white solid (0.0203 g, 93%).

LCMS: R.t. 0.85 min ES+ 343 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.94 (s, 1H); 8.75 (s, 1H); 7.63 (s, 1H);6.81 (dd, J=6.2, 8.0 Hz, 1H); 4.62-4.57 (m, 1H); 4.31 (d, J=3.8 Hz, 2H);4.19 (dd, J=3.6, 6.5 Hz, 1H); 2.82 (q, J=7.5 Hz, 2H); 2.72-2.61 (m, 1H);2.42-2.33 (m, 1H); 1.36 (t, J=7.5 Hz, 3H).

Example 87((2R,3S,4R,5R)-5-{6-[(3,5-Difluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-146)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-ethynyl-3,5-difluorobenzene in step c andDCM as the solvent in step e.

LCMS: R.t. 1.42 min ES+ 468 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO+D₂O): δ 8.97 (s, 1H); 8.80 (s, 1H); 7.55-7.35(m, 3H); 6.08 (d, J=5.1 Hz, 1H); 4.68 (t, J=5.1 Hz, 1H); 4.36-4.15 (m,4H).

Example 88((2R,3S,4R,5R)-5-{6-[(2,4-Difluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-110)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-ethynyl-2,4-difluorobenzene in step c andDCM as the solvent in step e.

LCMS: R.t. 1.38 min ES+ 468 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.99 (s, 1H); 8.83 (s, 1H); 7.88 (dd, J=8.5Hz, J=6.4 Hz, 1H); 7.60 (s, 2H); 7.55 (dt, J=9.6 Hz, J=2.5 Hz, 1H); 7.28(dt, J=8.5 Hz, J=2.6 Hz, 1H); 6.10 (d, J=5.0 Hz, 1H); 5.70 (bs, 1H);5.50 (bs, 1H); 4.69 (t, J=5.0 Hz, 1H); 4.35-4.19 (m, 4H).

Example 89((2R,3S,4R,5R)-5-{6-[(3-Chlorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-134)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-chloro-3-ethynylbenzene in step c and DCMas the solvent in step e.

LCMS: R.t. 1.01 min ES+ 466 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 8.93 (s, 1H); 8.78 (s, 1H); 7.74 (t, J=1.7Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.58 (dq, J=1.0, 1.1, 8.2 Hz, 1H); 7.54(s, 2H); 7.50 (t, J=7.9 Hz, 1H); 6.04 (d, J=5.1 Hz, 1H); 5.65 (d, J=5.6Hz, 1H); 5.44 (d, J=5.2 Hz, 1H); 4.63 (q, J=5.0 Hz, 1H); 4.30-4.13 (m,4H).

Example 90((2R,3S,4R,5R)-5-{6-[(3-Bromophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-103)

The title compound was prepared following the procedure described inExample 67, steps c-f using 1-bromo-3-ethynylbenzene in step c and DCMas the solvent in step e.

LCMS: R.t. 1.01 min ES+ 512 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 8.99 (s, 1H); 8.84 (s, 1H); 7.92 (t, J=1.7Hz, 1H); 7.77 (d, J=8.1 Hz, 1H); 7.74 (d, J=7.9 Hz, 1H); 7.60 (s, 2H);7.49 (t, J=7.9 Hz, 1H); 6.10 (d, J=5.1 Hz, 1H); 5.70 (bs, 1H); 5.50 (bs,1H); 4.69 (bs, 1H); 4.38-4.18 (m, 4H).

Example 91 [(2R,3S,5R)-3-hydroxy-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-2-yl]-methyl sulfamate (I-142) Step a:(2R,3S,5R)-2-{[(4-methylbenzoyl)oxy]methyl}-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-3-yl4-methylbenzoate

To a solution of 5-azaindole (0.152 g, 1.29 mmol) in AcCN (8 mL) wasadded NaH (60% in oil, 0.034 g, 1.42 mmol). The reaction was stirred for45 minutes at r.t. then1-α-chloro-2-deoxy-3,5-bis(p-toluoyl)-α-D-ribofuranosyl chloride (0.500g, 1.29 mmol) (Zhang, W.; Ramasamy, K. S.; Averett, D. R. NucleosidesNucleotides, 1999, 18, 2357-2365) was added in three portions. Thereaction was heated to 50° C. for 1.5 hours. The reaction mixture wasfiltered through a pad of celite with EtOAc, concentrated and theresidue was purified by flash chromatography (20 to 100% EtOAc/hexanes)to yield the product (0.248 g, 41%).

LCMS: R.t. 2.09 min ES+ 471 (formic acid).

Step b:(2R,3S,5R)-2-(hydroxymethyl)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-3-ol

To a solution of(2R,3S,5R)-2-{[(4-methylbenzoyl)oxy]methyl}-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-3-yl-4-methylbenzoate(0.764 g, 1.62 mmol) in methanol (30 mL) was added amberlyst A-26 (—OH)resin (7 g) and the suspension was stirred at r.t. overnight. Themixture was filtered with MeOH and concentrated. The residue waspurified by flash chromatography (0 to 10% MeOH/DCM) to yield theproduct (0.762 g, 93%).

LCMS: R.t. 0.28 min ES+ 235 (formic acid).

Step c:(2R,3S,5R)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)-2-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3-ol

To a solution of(2R,3S,5R)-2-(hydroxymethyl)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-3-ol(0.348 g, 1.49 mmol) and imidazole (0.228 mg, 3.35 mmol) in DMF (3.0 mL)at 0° C. was added dropwise triisopropylsilyl chloride (0.29 mL, 2.24mmol). The solution was diluted with water and brine and extracted withEtOAc (4×). The organic layer was concentrated and the residue waspurified by flash chromatography (20 to 100% EtOAc/hexanes) to yield theproduct (0.443 g, 76%).

LCMS: R.t. 1.35 min ES+ 391 (formic acid).

Step d:(2R,3S,5R)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)-2-{[(triisopropylsilyl)oxy]methyl}-tetrahydrofuran-3-ylacetate

To a solution of(2R,3S,5R)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)-2-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3-ol(0.487 g, 1.25 mmol) and a catalytic amount of DMAP in pyridine (1.6 mL)at 0° C. was added acetic anhydride (0.130 mL, 1.38 mmol) dropwise. Thereaction was stirred overnight, concentrated, dissolved in EtOAc, washedwith 1 M aq HCl (1×), water (1×) and brine (1×). The combined organicswere washed with water (2×), dried (Na₂SO₄), filtered, and concentratedto give the title compound (0.464 g, 95%) which was used without furtherpurification.

LCMS: R.t. 1.49 min ES+ 433 (formic acid).

Step e:[(2R,3S,5R)-3-hydroxy-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)tetrahydrofuran-2-yl]methylsulfamate (I-142)

The title compound was prepared as described in example 40 steps e-gusing(2R,3S,5R)-5-(1H-pyrrolo[3,2-c]pyridin-1-yl)-2-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3-ylacetate.

LCMS: R.t. 0.28 min ES+ 314 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.77 (s, 1H); 8.19 (d, J=6.0 Hz, 1H); 7.63(d, J=3.5 Hz, 1H); 7.61 (d, J=6.0 Hz, 1H); 6.73 (d, J=3.5 Hz, 1H); 6.51(dd, J=5.9 Hz, 8.1 Hz, 1H); 4.58-4.55 (m, 1H); 4.27 (d, J=3.8 Hz, 2H);4.19 (dd, J=3.6, 6.6 Hz, 1H); 2.65-2.58 (m, 1H); 2.42-2.37 (m, 1H).

Example 92[(2R,3S,5R)-3-Hydroxy-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-2-yl]methylsulfamate (I-144) Step a:(2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate

The title compound was prepared as described in Example 91 step a using4-chloropyrrolo[2,3-d]pyrimidine (0.395 g, 2.57 mmol) and purified byflash chromatography (0 to 20% EtOAc/hexanes) (1.07 g, 82%)

LCMS: R.t. 2.41 min ES+ 506 (formic acid).

Step b(2R,3S,5R)-2-(hydroxymethyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-3-ol

The title compound was prepared as described in Example 91 step b using(2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate (0.400 g, 0.791 mmol) to yield the product as a whitesolid (0.210 g, 100%).

LCMS: R.t. 1.08 min ES+ 266 (formic acid).

Step c:[(2R,3S,5R)-3-Hydroxy-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-2-yl]methylsulfamate (I-144)

The title compound was prepared as described in Example 91 steps c-eusing(2R,3S,5R)-2-(hydroxymethyl)-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-furan-3-ol.

LCMS: R.t. 1.15 min ES+ 345 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.44 (s, 1H); 7.58 (bs, 2H); 6.66 (dd,J=6.6 Hz, J=6.7 Hz, 1H); 6.60 (d, J=3.7 Hz, 1H); 5.54 (d, J=4.3 Hz, 1H);4.45-4.35 (m, 1H); 4.20 (dd, J=4.3 Hz, J=4.1 Hz, 1H); 4.10 (dd, J=5.6Hz, J=3.5 Hz, 1H); 4.04 (s, 3H); 2.66-2.54 (m, 1H); 2.34-2.23 (m, 2H).

Example 93((2R,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methylsulfamate (I-136) Step a:(2R,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate

A solution of(2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate (0.355 g, 0.702 mmol) in n-butanol (1 mL),(S)-(+)-1-aminoindan (0.23 mL, 1.77 mmol) and DIPEA (0.4 mL, 2.36 mmol)was microwave irradiated at 190° C. for 1200 seconds. The solution wasconcentrated and the residue was purified by flash chromatography (0 to20% EtOAc/hexanes) to yield the product as a pale yellow foam (0.272 g,64%).

LCMS: R.t. 2.04 min ES+ 603 (formic acid).

Step b:((2R,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-hydroxytetrahydrofuran-2-yl)methylsulfamate (I-136)

The title compound was prepared as described in Example 91 steps b-eusing(2R,3S,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate.

LCMS: R.t. 1.16 min ES+ 446 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.20 (s, 1H); 7.85 (d, J=8.73 Hz, 1H);7.59-7.35 (m, 4H); 6.71 (d, J=3.5 Hz, 1H); 6.60 (dd, J=6.4 Hz, 7.0 Hz,1H); 5.98-5.85 (m, 1H); 5.51 (d, J=4.2 Hz, 1H); 4.44-4.33 (m, 1H);4.25-3.98 (m, 3H); 3.09-2.80 (m, 2H); 2.46-2.37 (m, 1H); 2.32-2.17 (m,1H); 2.06-1.88 (m, 1H).

Example 94((2R,3S,4R,5R)-5-{6-[(anilinocarbonyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-108) Step a:((3aR,4R,6R,6aR)-6-{6-[(anilinocarbonyl)amino]-9H-purin-9-yl}-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methylacetate

To a solution of[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate (0.200 g, 0.572 mmol) in AcCN (3 mL) was added phenylisocyanate(0.068 g, 0.572 mmol) dropwise. The white mixture was stirred for twohours at ambient temperature, overnight at 50° C. and then concentratedto give the title compound (0.268 g, 100%).

LCMS: R.t. 1.86 min ES+ 469 (formic acid).

Step b:((2R,3S,4R,5R)-5-{6-[(anilinocarbonyl)amino]-9H-purin-9-yl}-3,4-dihydroxy-tetrahydrofuran-2-yl)methylsulfamate (I-108)

The title compound was prepared following the procedure described inExample 67, steps d-f using((3aR,4R,6R,6aR)-6-{6-[(anilinocarbonyl)amino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylacetate.

LCMS: R.t. 1.34 min ES+ 466 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 11.76 (s, 1H); 10.22 (s, 1H); 7.64 (bs,1H); 7.62 (bs, 2H); 7.36 (dd, J=7.7 Hz, J=8.0 Hz, 2H); 7.09 (t, J=7.4Hz, 1H); 6.05 (d, J=5.2 Hz, 1H); 4.66 (t, J=5.2 Hz, 1H); 4.36-4.16 (m,4H).

Example 95[(2R,3S,5R)-3-hydroxy-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]methylsulfamate (I-118) Step a:(2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate

The title compound was prepared as described for example 91 step a using4-chloropyrrolo[2,3-d]pyrimidine.

LCMS: R.t. 2.43 min ES+ 506 (formic acid).

Step b:(2R,3S,5R)-2-{[(4-methylbenzoyl)oxy]methyl}-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3-yl4-methylbenzoate

A suspension of(2R,3S,5R)-5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-{[(4-methylbenzoyl)oxy]methyl}tetrahydrofuran-3-yl4-methylbenzoate (480 mg, 0.95 mmol), NaHCO₃ (96 mg, 1.14 mmol) and 54mg wet Pd(OH)₂/C (20% Pd dry weight) in ethanol/EtOAc (6 mL, 5:1) wasstirred under an atmosphere of hydrogen for 26 hours. The suspension wasfiltered through celite with methanol/EtOAc, concentrated, and the cruderesidue (450 mg, >99%) was used without further purification.

LCMS: R.t. 2.20 min ES+ 472 (formic acid).

Step c:[(2R,3S,5R)-3-hydroxy-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]-methylsulfamate (I-118)

The title compound was prepared as described for example 91 steps b-eusing(2R,3S,5R)-2-{[(4-methylbenzoyl)oxy]methyl}-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-3-yl4-methylbenzoate.

LCMS: R.t. 1.72 min ES+ 315 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 9.02 (s, 1H); 8.80 (s, 1H); 7.77 (s, 1H);7.58 (bs, 2H); 6.81-6.67 (m, 2H); 5.56 (s, 1H); 4.41 (s, 1H); 4.29-4.00(m, 3H); 2.71-2.57 (m, 1H); 2.39-2.24 (m, 1H).

Example 96[(2R,3S,5R)-3-hydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl]-methylsulfamate (I-93) Step a:(2R,3S,5R)-5-(6-amino-9I-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-tetrahydrofuran-3-ol

To a solution of dry(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol(3.78 g, 15.04 mmol) and imidazole (2.46 g, 36.1 mmol) in DMF (20 mL)was added TBSCl (2.38 g, 15.80 mmol) and the solution was stirred atr.t. for 4 hours. The reaction mixture was diluted with water (100 mL),and extracted with EtOAc (3×100 mL). The combined organics were dried(Na₂SO₄) and concentrated. The product was isolated as a white solid(4.138 g, 75%) and was used without further purification.

LCMS: R.t. 1.31 min ES+ 366 (formic acid)

Step b:(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-tetrahydrofuran-3-ylacetate

To a solution of(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-ol(4.14 g, 11.3 mmol) and catalytic amount of DMAP in pyridine (11.3 mL)at 0° C. was added slowly acetic anhydride (1.12 mL, 11.89 mmol). Thesolution was stirred while warming to r.t. for 5 hours. The reaction wasquenched with 1 N HCl solution (70 mL) and extracted with EtOAc (3×100mL). The combined organics were washed with saturated aq CuSO₄ solution(50 mL) and dried (Na₂SO₄). A white solid was isolated upon removing thesolvent (4.143 g, 90%) and the crude material was used without furtherpurification.

LCMS: R.t. 1.61 min ES+ 409 (formic acid)

Step c:(2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-tetrahydrofuran-3-ylacetate

To a solution of(2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl-(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-ylacetate (2.00 g, 4.91 mmol) in CH₂Br₂ (98.2 mL) was added TMSBr (0.717mL, 5.55 mmol) and t-butylnitrite (3.98 mL, 33.4 mmol). The reactionmixture was stirred at r.t. for 3 hours then slowly poured into 50 mL ofa 1:1 mixture of saturated aq NaHCO₃:CH₂Cl₂. The organic layer waswashed with water (50 mL), brine (50 mL), dried (Na₂SO₄) andconcentrated. The crude product was purified by flash chromatography (0to 30% EtOAc/hexanes) to obtain the title compound as a yellow oil (1.26g, 55%).

LCMS: R.t. 2.16 min ES+ 473 (formic acid).

Step d:(2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(6-phenyl-9H-purin-9-yl)-tetrahydrofuran-3-ylacetate

A flame dried flask was charged with Pd(OAc)₂ (0.0185 g, 0.0823 mmol),2-(dicyclohexylphosphino)biphenyl (0.0433 g, 0.123 mmol), phenyl boronicacid (0.151 g, 1.23 mmol), and K₃PO₄ under an atmosphere of argon. Asolution of(2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-ylacetate (0.388 g, 0.823 mmol) in dry dioxane (5.49 mL) was added to themixture and the solution was stirred at 90° C. overnight. The reactionmixture was filtered through celite with CH₂Cl₂, concentrated andpurified by flash chromatography (10 to 30% EtOAc/hexanes) to afford thetitle compound as a clear oil (0.247 g, 64%).

LCMS: R.t. 2.39 min ES+ 469.5 (formic acid)

Step e:[(2R,3S,5R)-3-hydroxy-5-(6-phenyl-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-93)

The title compound was prepared as described in Example 40 steps e-g.

LCMS: R.t. 1.31 min ES+ 392 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 9.02 (s, 1H); 8.84-8.81 (m, 3H); 7.64-7.56(m, 5H); 6.58 (t, J=6.8 Hz, 1H); 5.60 (bs, 1H); 4.54 (m, 1H); 4.31-4.27(m, 1H); 4.22-4.18 (m, 1H); 4.15-4.12 (m, 1H); 2.90 (m, 1H); 2.45 (m,1H).

Example 97{(2R,3S,5R)-3-hydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methylsulfamate (I-92) Step a:(2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-3-ylacetate

To a solution of(2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-ylacetate (1.26 g, 2.67 mmol), CuI (0.102 g, 0.534 mmol), and Pd(PPh₃)₂Cl₂(0.187 g, 0.267 mmol) in DMF was added DIPEA (0.930 mL, 5.34 mmol) andphenylacetylene (1.17 mL, 10.69 mmol). The mixture was stirred at 75° C.for 1 hour then concentrated. The residue was dissolved in CH₂Cl₂ (70mL) and washed with saturated aq EDTA.Na₂ (3×50 mL). The combinedorganics were dried (Na₂SO₄) and concentrated. The dark crude oil waspurified by flash chromatography (40% EtOAc/hexanes) to afford the titlecompound (1.2 g, 91%).

LCMS: R.t. 2.37 min ES+ 493 (formic acid)

Step b:{(2R,3S,5R)-3-hydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}-methylsulfamate (I-92)

The title compound was prepared as described in Example 40 steps e-g.

(LCMS: R.t. 1.28 min ES+ 416 (formic acid)

¹H NMR (300 Mhz, CD₃CN): δ 8.91 (s, 1H); 8.47 (s, 1H); 7.72 (m, 2H);7.51 (m, 3H); 6.52 (t, J=6.5 Hz, 1H); 5.79 (bs, 2H); 4.63 (m, 1H);4.39-4.28 (m, 2H); 4.21 (m, 1H); 2.92-2.83 (m, 1H); 2.56-2.47 (m, 1H).

Example 98[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[2-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-113) Step a:[(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl]methylsulfamate

To a solution of((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (645 mg, 1.59 mmol) in 2-butanone (30.0 mL) was added NaI(4.77 g, 31.79 mmol). The reaction was cooled to −10° C. andtrifluoroacetic acid (612 μL, 7.94 mmol) was added. The reaction wasstirred for 4.5 hours, quenched with saturated aq NaHCO₃ and extractedwith DCM. The crude product was purified by flash chromatography (40%EtOAc/DCM) to isolate the title compound (0.642 g, 81%).

LCMS: R.t. 2.07 min ES+ 498 (formic acid)

Step b:[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-{[2-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate

To a solution of[(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate (0.200 g, 0.402 mmol) in DMF (7 mL) was added DIPEA (0.176 mL,1.01 mmol), 1-ethynyl-2-trifluoromethyl-benzene (0.224 mL, 1.61 mmol),CuI (0.0191 g, 0.101 mmol), and Pd(PPh₃)₂Cl₂ (0.0282 g, 0.0402 mmol).The mixture was stirred at r.t. for 50 min, diluted with DCM (25 mL) andwashed with saturated aq EDTA.Na₂ (3×25 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography (15 to 50% EtOAc/DCM)to isolate the title compound (0.185 g, 85%).

Step c:[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[2-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-113)

[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-{[2-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate (0.185 g, 0.343 mmol) was stirred in 3 mL of 90% TFA/H₂O for 4h at r.t. The solvent was removed and the crude product was purified byflash chromatography (1 to 10% MeOH/CH₂Cl₂) to isolate the titlecompound (0.0882 g, 52%).

LCMS: R.t. 1.46 min ES+ 500 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 9.00 (s, 1H); 8.84 (s, 1H); 7.83-7.57 (m,4H); 6.11 (d, J=5.0 Hz, 1H); 5.71 (bs, 1H); 5.50 (bs, 1H); 4.68 (m, 1H);4.43-4.20 (m, 4H).

Example 99((2R,3S,4R,5R)-5-{6-[(4-chlorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-91)

The title compound was prepared as described in Example 98 steps a-cusing 1-chloro-4-ethynylbenzene in step b.

LCMS: R.t. 1.46 min ES+ 466 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): S 8.98 (s, 1H); 8.83 (s, 1H); 7.76-7.72 (m,2H); 7.61-7.58 (m, 4H); 6.10 (d, J=5.3 Hz, 1H); 5.71 (d, J=5.8 Hz, 1H);5.50 (d, J=5.5 Hz, 1H); 4.69 (q, J=5.0, 5.5 Hz, 1H); 4.34-4.20 (m, 4H).

Example 100((2R,3S,4R,5R)-5-{6-[(2-bromophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-140)

The title compound was prepared as described in Example 98, steps a-c,using 1-bromo-2-ethynylbenzene in step b.

LCMS: R.t. 1.41 min ES+ 510 (formic acid)

¹H-NMR (400 MHz, CD₃OD): δ 8.14 (s, 1H); 7.94 (s, 1H); 7.06 (dd, J=7.5,1.8 Hz, 1H); 6.94 (dd, J=7.8, 1.3 Hz, 1H); 6.68-6.64 (m, 1H); 6.61-6.57(m, 1H); 5.42 (d, J=4.8 Hz, 1H); 3.98 (t, J=5.0 Hz, 1H); 3.67-3.62 (m,2H); 3.59-3.53 (m, 2H).

Example 101((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(4-methoxyphenyl)ethynyl]-9H-purin-9-yl}tetrahydrofuran-2-yl)methylsulfamate (I-123)

The title compound was prepared as described in Example 98, steps a-c,using 4-ethynylanisole in step b.

LCMS: R.t. 1.34 min ES+ 462 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 8.93 (s, 1H); 8.79 (s, 1H); 7.68-7.65 (m,2H); 7.60 (s, 1H); 7.10-7.06 (m, 2H); 6.10 (d, J=5.0 Hz, 1H); 5.70 (d,J=5.5 Hz, 1H); 5.50 (d, J=5.5 Hz, 1H); 4.71-4.67 (m, 1H); 4.34-4.19 (m,4H).

Example 102((2R,3S,4R,5R)-5-{6-[(2-fluorophenyl)ethynyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-152)

The title compound was prepared as described in Example 98, steps a-c,using 1-ethynyl-2-fluorobenzene in step b.

LCMS: R.t. 1.33 min ES+ 450 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 8.99 (s, 1H); 8.83 (s, 1H); 7.82-7.77 (m,1H); 7.66-7.58 (m, 2H); 7.48-7.34 (m, 2H); 6.11 (d, J=5.02 Hz, 1H);4.71-4.67 (m, 1H); 4.35-4.20 (m, 4H).

Example 103 (2R,3S,4R,5R)Sulfamic acid5-(6-cyclopropylethynyl-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethylester (I-95) Step a: (3aR,4R,6R,6aR) Sulfamic acid6-(6-cyclopropylethynyl-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylester

A solution of (3aR,4R,6R,6aR) sulfamic acid6-(6-iodo-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylester (172.0 mg, 0.277 mmol), cyclopropyl acetylene (131 μL, 1.11 mmol),CuI (13.2 mg, 0.0692 mmol), Pd(PPh₃)₂Cl₂ (19.4 mg, 0.0277 mmol) andDIPEA (120.5 μL, 0.6918 mmol) in tetrahydrofuran (5.0 mL, degassed withnitrogen) was stirred for 60 minutes at r.t. The reaction wasconcentrated and taken up in DCM. This was washed with saturated aqEDTA.Na₂. The layers were separated, the organic phase was concentrated,and the residue was purified by flash chromatography (0 to 100%EtOAc/DCM) to yield the product (90 mg, 75%).

LCMS: R.t. 2.26 min ES+ 436 (ammonium acetate)

Step b: (2R,3S,4R,5R)Sulfamic acid5-(6-cyclopropylethynyl-purin-9-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethylester (I-95)

The title compound was prepared as described in Example 98, steps c.

LCMS: R.t. 1.07 min ES+ 396 (formic acid)

¹H-NMR (400 MHz, CD₃OD): δ 8.80 (s, 1H), 8.67 (s, 1H), 6.19 (d, J=4.9Hz, 1H), 4.77 (t, J=5.0 Hz, 1H), 4.48-4.43 (m, 2H), 4.41-4.34 (m, 2H),1.70 (tt, J=5.2 Hz, 8.0 Hz, 1H), 1.11-1.02 (m, 4H).

Example 104{(2R,3S,5R)-5-[6-(benzylamino)-9H-purin-9-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-102)

The title compound was prepared as described in Example 40 steps a-gusing benzylamine in step d.

LCMS: R.t. 1.19 min ES+ 421 (formic acid)

¹H-NMR (400 MHz, d₆-DMSO): δ 8.39 (bs, 1H); 8.31 (s, 1H); 8.21 (s, 1H);7.53 (bs, 2H); 7.34-7.19 (m, 5H); 6.40 (t, J=6.8 Hz, 1H); 5.54 (bs, 1H);4.70 (bs, 2H); 4.48 (bs, 1H); 4.25 (m, 1H); 4.14 (m, 1H); 4.07 (m, 1H);2.82 (m, 1H); 2.34 (m, 1H).

Example 105{(2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-128) Step a:N-[7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]-oxy]methyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide

To a solution ofN-{7-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-furan-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide(0.579 g, 1.63 mmol) and imidazole (0.534 g, 7.84 mmol) in DMF (4.1 mL)was added TBSCl (0.675 g, 4.48 mmol) and the mixture was stirred at r.t.overnight. Additional TBSCl (0.300 g, 1.99 mmol) was added and thesolution stirred for 3 h. The reaction mixture was diluted with H₂O (30mL) and extracted with EtOAc (3×30 mL). The combined organics werewashed with brine (60 mL), dried (Na₂SO₄), filtered, and concentrated.The crude material was purified by flash chromatography (0 to 30%EtOAc/DCM) to afford the title compound (0.839 g, 88%).

LCMS: R.t. 3.36 min ES+ 583 (formic acid)

Step b:N-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide

To a solution ofN-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-benzamide(1.06 g, 1.82 mmol) in 18 mL THF/pyridine (1:1) was added approximately20 drops of hydrofluoridic acid in pyridine. The mixture was stirred atr.t. for 30 h. The reaction was quenched by slowly adding to saturatedaq NaHCO₃ (100 mL) and the solution was extracted with EtOAc (3×50 mL).The combined organics were washed with saturated aq Cu(SO₄)₂ (50 mL) andsaturated aq EDTA.Na₂. The combined organics were dried (Na₂SO₄),filtered, and concentrated. The residue was purified by flashchromatography (15 to 50% EtOAc/hexanes) to isolate the title compoundas a white foam (0.264 g, 31%).

LCMS: R.t. 2.09 min ES+ 469 (formic acid).

Step c:((2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methylsulfamate

Using essentially the same procedure as example 43 step f,N-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide(0.524 g, 1.12 mmol) was reacted with chlorosulfonamide and the productwas purified by flash chromatography (20 to 50% EtOAc/hexanes) to affordthe title compound as a white foam (0.292 g, 48%).

LCMS: R.t. 2.02 min ES+ 548 (formic acid)

Step d:{(2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-128)

To a solution of((2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methylsulfamate (0.292 g, 0.533 mmol) in 5.4 mL pyridine/THF (1:1) was addedapproximately 5 drops of hydrofluoridic acid in pyridine. The solutionwas stirred at r.t. overnight, quenched by slowly adding saturated aqNaHCO₃ (20 mL) and extracted with DCM (2×25 mL) and EtOAc (25 mL). Theorganics were combined, dried (Na₂SO₄), filtered, and concentrated. Thecrude material was purified by flash chromatography (1 to 10% MeOH/DCM)to afford the final compound (0.177 g, 77%).

LCMS: R.t. 1.28 min ES+ 434 (formic acid).

¹H-NMR (400 MHz, CD₃CN) δ 9.23 (bs, 1H); 8.55 (s, 1H); 8.02 (d, J=7.5Hz, 2H); 7.66-7.53 (m, 3H); 7.47 (d, J=3.8 Hz, 1H); 6.91 (d, J=3.5 Hz,1H); 6.77 (t, J=6.8 Hz, 1H); 5.77 (bs, 2H); 4.57-4.53 (m, 1H); 4.33-4.24(m, 2H); 4.16-4.13 (m, 1H); 3.62 (d, J=4.3 Hz, 1H); 2.68-2.61 (m, 1H);2.43-2.37 (m, 1H).

Example 106((2R,3S,4R,5R)-5-{6-[(4-bromobenzoyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-112) Step a:4-bromo-N-{9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}benzamide

[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methanol(0.400 g, 1.30 mmol) was dried by co-evaporation with pyridine, thensuspended in dry pyridine (6.5 mL). TMSCl (0.330 mL, 2.60 mmol) wasadded and the mixture was stirred for 15 min. 4-Bromobenzoylchloride(0.342 g, 1.56 mmol) was added to the mixture and stirred for 2 h. Thesolution was cooled to 0° C. and 1 mL of H₂O was added. After 5 min a29% NH₃ aq solution (0.847 mL) was added and the reaction mixture wasstirred for 30 min while warming to r.t. The mixture was thenconcentrated and the residue was diluted with H₂O (40 mL). The productwas extracted with EtOAc (60 mL) and concentrated. The crude materialwas purified by flash chromatography (65 to 100% EtOAc/hexanes) toafford the title compound (0.305 g, 49%).

LCMS: R.t. 1.46 min ES+ 492 (formic acid)

Step b:(3aR,4R,6R,6aR)-6-{6-[(4-bromobenzoyl)amino]-9H-purin-9-yl}-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate

Using essentially the same procedure as example 39, step c,4-bromo-N-{9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}benzamide(0.305 g, 0.622 mmol) was reacted with chlorosulfonamide, and theproduct was purified by flash chromatography (50 to 100% EtOAc/hexanes)to afford the title compound (0.243 g, 69%).

LCMS: R.t. 1.57 min ES+ 571 (formic acid).

Step c:2R,3S,4R,5R)-5-{6-[(4-bromobenzoyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-112)

((3aR,4R,6R,6aR)-6-{6-[(4-bromobenzoyl)amino]-9H-purin-9-yl}-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsulfamate (0.243 g, 0.427 mmol) was stirred in 3 mL of 90% TFA in H₂Ofor 4 h. The solution was concentrated and MeOH was added to theresidue. The title compound precipitated out of the solution as a whitesolid (0.0794 g, 35%)

LCMS: R.t. 1.27 min ES+ 531 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 11.36 (s, 1H); 8.77 (s, 1H); 8.64 (s, 1H);7.98 (d, J=8.53 Hz, 2H); 7.77 (d, J=8.53 Hz, 2H); 7.62 (s, 2H); 6.08 (d,J=5.77 Hz, 1H); 5.74 (bs, 1H); 5.53 (bs, 1H); 4.72-4.67 (m, 1H);4.34-4.17 (m, 4H).

Example 107((2R,3S,4R,5R)-5-{6-[(4-chlorobenzoyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-119)

The title compound was prepared as described in Example 106 steps a-cusing 4-chlorobenzoylchloride in step a.

LCMS: R.t. 1.23 min ES+ 485 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ11.35 (s, 1H); 8.77 (s, 1H); 8.64 (s, 1H);8.08-8.04 (m, 2H); 7.65-7.61 (m, 4H); 6.09 (d, J=5.3 Hz, 1H); 5.73 (d,J=5.3 Hz, 1H); 5.52 (d, J=5.8 Hz, 1H); 4.72-4.67 (m, 1H); 4.34-4.17 (m,4H).

Example 108((2R,3S,4R,5R)-3,4-dihydroxy-5-{6-[(2-methoxybenzoyl)amino]-9H-purin-9-yl}tetrahydrofuran-2-yl)methylsulfamate (I-150)

The title compound was prepared as described in Example 106 steps a-cusing 2-methoxybenzoylchloride in step a.

LCMS: R.t. 1.17 min ES+ 481 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ11.14 (s, 1H); 8.72 (s, 1H); 8.67 (s, 1H);7.95 (dd, J=7.5, 1.5 Hz, 1H); 7.66-7.60 (m, 3H); 7.29 (d, J=8.3 Hz, 1H);7.16 (t, J=7.0 Hz, 1H); 6.08 (d, J=5.3 Hz, 1H); 4.69 (t, J=5.3 Hz, 1H);4.34-4.18 (m, 4H); 4.04 (s, 3H).

Example 109[(2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-3-hydroxy-4-methoxytetrahydro-furan-2-yl]methylsulfamate (I-99) Step a:(6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol

(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ylacetate (3.51 g, 6.14 mmol) (Kittaka, A.; Yamada, N.; Tanaka, H.;Nakamura, K. T.; Miyasaka, T. Nucleosides Nucleotides, 1996, 15,1447-1457) was stirred in 7N NH₃ in MeOH (2.33 mL) for 2.5 h. Themixture was then concentrated and the residue was purified by flashchromatography (20 to 50% EtOAc/hexanes) to give title compound as alight yellow foam (3.06 g, 92%).

LCMS: R.t. 2.72 min ES+ 529 (formic acid)

Step b:6-chloro-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine

To a suspension of(6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol(3.06 g, 5.79 mmol) and Cs₂CO₃ (18.86 g, 57.9 mmol) in DMF (58 mL) at 0°C. was added methyl iodide (3.60 mL, 57.9 mmol) dropwise and reactionwas stirred for 3 h while warming to r.t. The solution was diluted withCH₂Cl₂ (150 mL) and washed with saturated aq NH₄Cl. The aq layer wasextracted with CH₂Cl₂ (2×100 mL) and the combined organics were dried(Na₂SO₄), filtered, and concentrated. The crude material was purified byflash chromatography (5 to 30% EtOAc/hexanes) to afford the titlecompound (1.51 g, 48%).

LCMS: R.t. 3.14 min ES+ 543 (formic acid)

Step c:(2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)-4-methoxytetrahydrofuran-3-ol

To a solution of6-chloro-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine(1.31 g, 2.41 mmol) in THF/pyridine (12 mL, 1:1) was added approximately20 drops of hydrofluoric acid in pyridine. This solution was stirred atr.t. overnight. The reaction was diluted with EtOAc (10 mL) and quenchedwith saturated aq NaHCO₃. The aq layer was extracted with EtOAc (3×40mL) and the combined organics were dried (Na₂SO₄), filtered, andconcentrated. The crude material was purified by flash chromatography (0to 10% MeOH/DCM) to afford the title compound (0.690 g, 74%).

LCMS: R.t. 0.94 min ES+ 301 (formic acid)

Step d:[(2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-3-hydroxy-4-methoxytetrahydrofuran-2-yl]methylsulfamate (I-99)

The title compound was prepared as described in Example 40 steps a-b andexample 40 steps e-g.

LCMS: R.t. 1.08 min ES+ 380 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.76 (s, 1H); 8.63 (s, 1H); 6.69 (d, J=5.3Hz, 1H); 4.49 (t, J=4.8 Hz, 1H); 4.45-4.37 (m, 2H); 4.23-4.18 (m, 1H);4.13-4.10 (m, 1H); 3.26 (s, 3H).

Example 110[(2R,3S,5R)-5-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-3-hydroxytetrahydro-furan-2-yl]methylsulfamate (I-106) Step a:(2R,3S,5R)-5-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol

The title compound was prepared as described in Example 91 steps a-busing 4-chloro-1H-pyrrolo[3,2-c]pyridine (Bilodeau, M. T.; Manley, P.J.; Hartman, G. D. Tyrosine Kinase Inhibitors. International PatentWO03009852 A1, Feb. 6, 2003) in step a.

LCMS: R.t. 1.03 min ES+ 269 (formic acid)

Step b:[(2R,3S,5R)-5-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-3-hydroxytetrahydrofuran-2-yl]methylsulfamate (I-106)

The title compound was prepared as described in Example 40 steps a-b andexample 40 steps e-g starting with(2R,3S,5R)-5-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol.

LCMS: R.t. 1.09 min ES+ 346 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.01 (d, J=6.0 Hz, 1H); 7.69 (d, J=3.8 Hz,1H); 7.61 (dd, J=6.0, 0.8 Hz, 1H); 6.72 (d, J=3.5 Hz, 1H); 6.51-6.46 (m,1H); 4.60-4.55 (m, 1H); 4.30-4.27 (m, 2H); 4.23-4.19 (m, 1H); 2.64-2.56(m, 1H); 2.45-2.39 (m, 1H).

Example 111{(2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-143) Step a:1-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}-methyl)tetrahydrofuran-2-yl]-4-chloro-1H-pyrrolo[3,2-c]pyridine

A solution of(2R,3S,5R)-5-(4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol(1.41 g, 0.945 mmol), imidazole (0.433 g, 6.36 mmol), and TBSCl (0.533g, 3.54 mmol) was stirred in DMF (13.2 mL) at r.t. for 4.5 h. Thesolution was diluted with water (40 mL) and extracted with EtOAc (3×50mL). The combined organics were washed with brine, dried (Na₂SO₄),filtered, and concentrated. The crude material was purified by flashchromatography (0 to 25% EtOAc/hexanes) to afford the title compound(0.686 g, 98%).

LCMS: R.t. 3.30 min ES+ 497 (formic acid).

Step b:((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methanol

A flame dried Schlenk flask was charged with1-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-2-yl]-4-chloro-1H-pyrrolo[3,2-c]pyridine(0.343 g, 0.690 mmol), 1,4 dioxane (1.40 mL), benzylamine (0.226 mL,2.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0126 g, 0.0138mmol), 2-(dicyclohexylphosphino)biphenyl (0.00686 g, 0.0196 mmol), andsodium tert-butoxide (0.186 g, 1.93 mmol). The tube purged with N2 (3×),sealed and the mixture was heated at 95° C. overnight. The reactionmixture was cooled to r. t., diluted with CH₂Cl₂ (20 mL) and washed withwater (20 mL). The aq layer was extracted with CH₂Cl₂ (3×20 mL) and thecombined organics were dried (Na₂SO₄), filtered, and concentrated. Thecrude oil was purified by flash chromatography (10 to 40% EtOAc/hexanes)to give the title compound as a light yellow foam (0.313 g, 28%).

LCMS: R.t. 1.42 min ES+ 454 (formic acid).

Step c:((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methylsulfamate

Using essentially the same procedure as example 43, step f,((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methanol(0.0876 g, 0.193 mmol) was reacted with chlorosulfonamide, and theproduct was purified by flash chromatography (60 to 100% EtOAc/CH₂Cl₂)to afford the title compound (0.0300 g, 29%).

LCMS: R.t. 1.42 min ES+ 533 (formic acid).

Step d:{(2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-143)

To a solution of((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methylsulfamate (0.0300 g, 0.0563 mmol) in THF/pyridine (1 mL, 1:1) was addedhydrofluoric acid in pyridine (3 drops) and stirred overnight. Thereaction was diluted with EtOAc (5 mL) and quenched with saturated aqNaHCO₃ (10 mL). The aq layer was extracted with EtOAc (3×10 mL) and thecombined organics were dried (Na₂SO₄), filtered, and concentrated. Thecrude material was purified by preparative plate chromatography (10%MeOH/EtOAc) to give the final compound (0.00590 g, 25%).

LCMS: R.t. 1.03 min ES+ 419 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 7.60 (d, J=6.3 Hz, 1H); 7.40-7.19 (m, 6H);6.90 (dd, J=6.5, 0.8 Hz, 1H); 6.77 (d, J=3.3 Hz, 1H); 6.42-6.36 (m, 1H);4.72 (s, 2H); 4.57-4.52 (m, 1H); 4.29-4.25 (m, 2H); 4.20-4.16 (m, 1H);2.62-2.54 (m, 1H); 2.41-2.34 (m, 1H).

Example 112{(2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-[6-(2-phenylethyl)-9H-purin-9-yl]-tetrahydrofuran-2-yl}methylrel-sulfamate (I-147) Step a:(2R,3R,4S,5R)-4-fluoro-5-[6-(2-phenylethyl)-9H-purin-9-yl]-2-[(trityloxy)methyl]-tetrahydrofuran-3-ylbenzoate

(2R,3R,4S,5R)-5-(6-Chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydrofuran-3-ylbenzoate (0.330 g, 0.520 mmol), tris(dibenzylideneacetone)dipalladium(0)(0.012 g, 0.013 mmol) and triphenylphosphine (0.027 g, 0.104 mmol) wereadded to a flame-dried flask under argon. Tetrahydrofuran (2.5 mL) wasadded followed by the dropwise addition of phenethylzinc bromide (2.08mL, 1.04 mmol). The mixture was heated at 50° C. for two hours. Thereaction was added to saturated aq NH₄Cl, extracted with DCM (3×), dried(Na₂SO₄), filtered, and concentrated. The residue was purified by flashchromatography (0 to 35% EtOAc/hexanes) to give the product (0.193 g,51%).

LCMS: R.t. 2.53 min ES+ 705 (formic acid)

Step b:{(2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydro-furan-2-yl}methylrel-sulfamate (I-147)

The title compound was prepared as described in Example 68 steps e-gusing(2R,3R,4S,5R)-4-fluoro-5-[6-(2-phenylethyl)-9H-purin-9-yl]-2-[(trityloxy)methyl]tetrahydro-furan-3-ylbenzoate.

LCMS: R.t. 1.38 min ES+ 438 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.82 (s, 1H); 8.52 (d, J=2.2 Hz, 1H);7.24-7.07 (m, 5H); 6.65 (dd, J=13.5 Hz, 3.8 Hz, 1H); 5.17 (ddd, J=51.8,3.7, 2.8 Hz, 1H); 4.58 (ddd, J=15.9, 3.1, 2.8 Hz, 1H); 4.39 (d, J=5.0Hz, 2H); 4.25 (q, J=4.6 Hz, 1H); 3.44 (dd, J=7.3, 5.9 Hz, 2H); 3.15 (dd,J=7.3, J=6.1 Hz, 2H).

Example 113N-({(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]-tetrahydrofuran-2-yl}methyl)sulfamide(I-115) Step a:N-{[(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide

To a solution ofN-({(3aR,4R,6R,6aR)-2,2-dimethyl-6-[6-chloro-9H-purin-9-yl]-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyl)sulfamide(0.3 g, 0.74 mmol) in 2-butanone (15 mL) was added NaI (2.22 g, 0.14mol) and trifluoroacetic acid (570 pt, 0.074 mol). The reaction mixturewas stirred at −10° C. for 3.5h quenched with saturated aq NaHCO₃ (20mL), extracted with DCM (3×25 mL) and the organic layers dried (Na₂SO₄)and concentrated. The residue was purified via flash chromatography (0to 60% EtOAc/DCM) to give the title compound (0.14 g, 61%).

LCMS: R.t. 1.26 min ES+ 497 (formic acid)

Step b:N-({(3aR,4R,6R,6aR)-2,2-dimethyl-6-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyl)sulfamide

To a solution ofN-{[(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide(0.14 g, 0.28 mmol) in DMF was added phenylacetylene (0.115 g, 1.13mmol), CuI (10.6 mg, 0.056 mmol), DIPEA (98 μL, 0.56 mmol) andPd(PPh₃)₂Cl₂ (10 mg, 0.028 mmol). The solution was stirred for 1 h atr.t. and concentrated. The residue was taken up in DCM, washed withsaturated aq EDTA.Na₂ (3×20 mL), dried (Na₂SO₄) concentrated andpurified by flash chromatography (20 to 60% EtOAc/DCM) to give the titlecompound (0.08 g, 60%).

LCMS: R.t. 1.60 min ES+ 471 (formic acid).

Step c:N-({(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(phenylethynyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methyl)sulfamide(I-115)

The title compound was prepared following the procedure described inExample 1, step d.

LCMS: R.t. 1.36 min ES+ 431 (formic acid)

¹H-NMR (300 MHz, d₆-DMSO): δ 8.94 (s, 1H); 8.89 (s, 1H) 7.72 (dd, J=9.4Hz, 2H); 7.53 (m, 3H); 6.99-6.97 (m, 1H); 6.61 (s, 2H); 6.01 (d, J=6.5Hz, 1H); 5.55 (d, J=6.0 Hz, 1H); 5.33 (d, J=4.2 Hz, 1H); 4.18 (m, 1H);4.12 (m, 1H).

Example 114{(2R,3S,4R,5R)-5-[6-({2-[(acetylamino)methyl]benzyl}amino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-148) Step a: N-[2-(aminomethyl)benzyl]acetamide

To a solution of tert-butyl[2-(aminomethyl)benzyl]carbamate (0.2 g, 0.93mmol) and triethylamine (260 μL, 1.9 mmol) in DCM (10 mL) was added Ac₂O(0.285 g, 0.00279 mol) dropwise and the reaction stirred for 2 h at r.t.The reaction was concentrated, the residue dissolved in EtOAc (20 mL)then washed with saturated aq NaHCO₃ (2×10 mL). The organic layer wasdried (Na₂SO₄) and concentrated to give the crude product (0.25 g, 90%).To a solution of this in DCM (5 mL) was added 2 mL of 4M HCl/dioxane andthe solution was stirred for 1 h. The reaction was concentrated to givethe title compound (0.16 g, 95%) which was used without furtherpurification.

LCMS: R.t. 1.08 min ES+ 179 (formic acid).

Step b:{(2R,3S,4R,5R)-5-[6-({2-[(acetylamino)methyl]benzyl}amino)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-148)

The title compound was prepared following the procedure described inExample 1, steps b-d, using N-[2-(aminomethyl)benzyl]acetamide in stepb.

LCMS: R.t. 1.08 min ES+ 508 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.08 (s, 1H); 8.04 (t, J=5.5 Hz, 1H); 7.97(s, 1H); 7.32 (s, 1H); 6.97 (m, 4H); 5.70 (d, J=5.3 Hz, 1H); 4.43 (m,2H); 4.14 (d, J=5.7 Hz, 2H); 3.97 (m, 5H); 1.64 (s, 3H).

Example 115((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-130) Step a: (1S)-N-methylindan-1-amine

To a solution of (S)-(+)-1-aminoindan (176 mg, 1.29 mmol) in THF (10.0mL) was added Et₃N (0.200 mL, 1.43 mmol) followed bydi-tert-butyldicarbonate (286 mg, 1.31 mmol). The mixture was stirredunder an atmosphere of nitrogen for 3 days, concentrated, diluted withDCM (100 mL), and washed with 0.1 N aq hydrochloric acid (50.0 mL) andaq NaCl. The organic layer was dried (MgSO₄), filtered and concentrated.The tan solid was taken up in tetrahydrofuran (10.0 mL) and to this wasadded with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF,5.80 mL). The mixture was heated at reflux for 6 hours, quenched withwater (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL).This was stirred for 10 minutes, filtered through celite, diluted withEtOAc (100 mL), dried (MgSO₄), filtered and concentrated. The residuewas purified via flash chromatography (0 to 100% EtOAc/hexanes to 10%MeOH/DCM) to afford the title compound as a black solid (146 mg, 77%).

LCMS: R.t. 0.83 min ES 148 (ammonium acetate).

Step b:[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl]methyltritylsulfamate

To a solution of[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate (13.4 g, 33.1 mmol) in DCM (330 mL) at r.t. was added DIPEA(11.5 mL, 66.2 mmol) followed by Ph₃CCl (9.23 g, 33.1 mmol). Thereaction was stirred at r.t. for 4 hours. The mixture was diluted withDCM, the layers were separated, and the organic layer was washed with 1NHCl followed by brine. The combined organic phases were dried (Na₂SO₄)and concentrated to yield the title compound as a white solid (17.6 g,82%).

LCMS: R.t. 2.07 min ES+ 648, ES− 646 (formic acid).

Step c:((3aR,4R,6R,6aR)-6-{6-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol

A suspension of (1S)-N-methylindan-1-amine (67.8 mg, 0.461 mmol),[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate (200 mg, 0.309 mmol) and DIPEA (0.160 mL, 0.919 mmol) inethanol (3.0 mL) was heated at 150° C. for 600 s using microwaveirradiation. The residue was purified via flash chromatography (0 to100% EtOAc/DCM) to afford the title compound as a brown oil (74.3 mg,55%).

LCMS: R.t. 1.93 min ES+ 438 (ammonium acetate).

Step d:((2R,3S,4R,5R)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-yl(methyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-130)

The title compound was prepared following the procedure described inExample 39 step c, using AcCN as the solvent and purification by HPLC.

LCMS: R.t. 1.46 min, ES+ 477 (ammonium acetate).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.34 (s, 1H); 8.32 (s, 1H); 7.61 (s, 2H);7.33 (d, J=7.3 Hz, 1H); 7.26 (dd, J=7.2, 7.2 Hz, 1H); 7.19 (dd, J=7.3,7.3 Hz, 1H); 7.10 (d, J=7.4 Hz, 1H); 6.01 (d, J=5.1 Hz, 1H); 5.75-5.61(m, 1H); 5.54-5.42 (m, 1H); 4.67-4.56 (m, 1H); 4.35-4.12 (m, 4H);3.13-2.99 (m, 1H); 2.98-2.79 (m, 2H); 2.46-2.36 (m, 1H); 2.19-2.03 (m,1H).

Example 116[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-isobutyl-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-98) Step a:[(3aR,4R,6R,6aR)-6-(6-isobutyl-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate

To a solution of[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate (320.0 mg, 0.87 mmol) and Pd(PPh₃)₄ (56 mg, 0.048 mmol) in THF(7 mL, 0.09 mol, degassed with nitrogen) was added a solution of 0.5 Misobutylzinc bromide in THF (2.60 mL) dropwise over 15 min. The reactionwas heated at 60° C. under an atmosphere of nitrogen for 1 hour, cooledand quenched with saturated aq NH₄Cl. This mixture was extracted withEtOAc, the combined organics were washed with saturated aq EDTA.Na₂,water, concentrated and then purified by flash chromatography (0 to 100%EtOAc/DCM) to yield the product (304 mg, 85%)

LCMS: R.t. 1.60 min ES+ 391 (formic acid).

Step b:[(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-isobutyl-9H-purin-9-yl)tetrahydrofuran-2-yl]-methylsulfamate (I-98)

The title compound was prepared as described in Example 67 steps d-f andpurified by HPLC.

LCMS: R.t. 1.08 min ES+ 388 (formic acid).

¹H-NMR (300 MHz) δ 8.81 (s, 1H); 8.60 (s, 1H); 6.17 (d, J=5.1 Hz, 1H);4.74 (t, J=5.1 Hz, 1H); 4.45-4.28 (m, 4H); 3.01 (d, J=7.3 Hz, 2H);2.37-2.23 (m, 1H); 0.94 (d, J=6.7 Hz, 6H).

Example 117((2R,3S,4R,5R)-3,4-dihydroxy-5-6-[(E)-2-phenylvinyl]-9H-purin-9-yltetrahydrofuran-2-yl)methylsulfamate (I-69) Step a:((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(E)-styryl-9H-purin-9-yl)-tetrahydro-furo[3,4-d][1,3]-dioxol-4-yl)methylacetate

Under an atmosphere of nitrogen, a solution of (3aR,4R,6R,6aR)aceticacid2,2-dimethyl-6-(6-vinyl-purin-9-yl)-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylester (340.0 mg, 0.94 mmol), Pd(OAc)₂ (21.2 mg, 0.094 mmol), DIPEA(493.0 μL, 2.83 mmol), and iodobenzene (132 μL, 1.18 mmol) in DMF (4.0mL, degassed with nitrogen) was stirred at 60° C. overnight. Thereaction was cooled and concentrated and the residue was purified byflash chromatography (0 to 100% EtOAc/hexanes) to yield the product (304mg, 74%).

LCMS: R.t. 1.94 min ES+ 437 (formic acid).

Step b:((2R,3S,4R,5R)-3,4-dihydroxy-5-6-[(E)-2-phenylvinyl]-9H-purin-9-yltetrahydrofuran-2-yl)methylsulfamate (I-69)

The title compound was prepared as described in Example 67 steps d-f.

LCMS: R.t. 2.10 min ES+ 434 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.90 (s, 1H); 8.76 (s, 1H); 8.40 (d, J=16.2Hz, 1H); 7.79 (d, J=7.2 Hz, 2H); 7.66 (d, J=16.2 Hz, 1H); 7.60 (bs, 2H);7.49-7.39 (m, 3H); 6.10 (d, J=5.2 Hz, 1H); 5.86-5.22 (bs, 2H); 4.70 (t,J=5.1 Hz, 1H); 4.35-4.18 (m, 4H).

Example 1182-((2R,3S,4R,5R)-5-6-[(3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)amino]-9H-purin-9-yl-3,4-dihydroxytetrahydrofuran-2-yl)ethanesulfonamide(I-100)

The title compound was prepared following the procedure described inExample 49 steps h-i, using 3,3-dimethylindan-1-amine in step h.

LCMS: R.t. 1.42 min ES+ 489 (ammonium acetate).

¹H-NMR (300 MHz, CD₃OD): δ 8.31 (s, 1H); 8.16 (s, 1H); 7.22 (m, 4H);5.94 (bs, 2H); 4.78 (t, J=5.4 Hz, 1H); 4.27 (t, J=5.3 Hz, 1H); 4.12 (dd,J=6.1, 12.1 Hz, 1H); 3.23 (dd, J=7.1, 15.2 Hz, 2H); 2.52 (dd, J=7.4,12.5 Hz, 1H); 2.29 (dd, J=7.3, 15.2 Hz, 2H); 1.91 (dd, J=8.5, 12.5 Hz,1H); 1.42 (s, 3H); 1.27 (s, 3H).

Example 119((2R,3S,4R,5R)-5-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-1H-imidazo[4,5-d]-pyridazin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methylsulfamate(I-139) Step a:(3aR,4R,6R,6aR)[6-(4-Chloro-imidazo[4,5-d]pyridazin-1-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol

A suspension of(2R,3R,4S,5R)-2-(4-chloro-1H-imidazo[4,5-d]pyridazin-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol(299.0 mg, 1.04 mmol) (Bussolari, J. C.; Ramesh, K.; Stoeckler, J. D.;Chen, S-F.; Panzica, R. P. J. Med. Chem. 1993, 36, 4113-4120),2,2-dimethoxypropane (640 μL, 5.2 mmol) and p-toluenesulfonic acidmonohydrate (199 mg, 1.05 mmol) in acetone (16 mL) was stirred overnightat room temperature. To this was added saturated aq NaHCO₃ (20 mL) andthe mixture was concentrated. The aqueous residue was extracted withCHCl₃ (4×50 mL) and the combined organics were dried (Na₂SO₄), filteredand concentrated to yield the product (340 mg, 100%).

LCMS: R.t. 1.08 min ES+ 327, 329 (formic acid).

Step b:((3aR,4R,6R,6aR)-6-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-1H-imidazo[4,5-d]-pyridazin-1-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)methanol

A solution of(3aR,4R,6R,6aR)[6-(4-Chloro-imidazo[4,5-d]pyridazin-1-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol1 (80.0 mg, 0.245 mmol), (S)-(+)-1-aminoindan (54.9 μL, 0.428 mmol) andDIPEA (74.6 μL, 0.428 mmol) in butanol (2.2 mL) was heated at 200° C.for 20 minutes using microwave irradiation. The reaction wasconcentrated and the residue purified by flash chromatography (0 to 20%EtOH/DCM) to yield the product (40 mg, 39%).

LCMS: R.t. 2.22 min ES+ 424 (formic acid).

Step c:((2R,3S,4R,5R)-5-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-1H-imidazo[4,5-d]-pyridazin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methylsulfamate(I-139)

The title compound was prepared as described in Example 67 steps e-f,and purified by preparative HPLC.

LCMS: R.t. 1.19 min ES+ 463 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 9.07 (s, 1H); 8.48 (s, 1H); 7.36 (d, J=7.4Hz, 1H); 7.29 (d, J=7.4 Hz, 1H); 7.24 (t, J=7.3 Hz, 1H); 7.18 (t, J=7.1Hz, 1H); 6.04 (d, J=6.3 Hz, 1H); 5.93 (t, J=7.2 Hz, 1H); 4.44-4.38 (m,4H); 4.33 (dd, J=2.6, 5.3 Hz, 1H); 3.10 (ddd, J=4.0, 8.6, 15.7 Hz, 1H);2.96 (td, J=8.1, 16.0 Hz, 1H); 2.78-2.70 (m, 1H); 2.05 (ddd, J=8.3,12.7, 15.8 Hz, 1H).

Example 120[(2R,3S,4R,5R)-5-(6-ethyl-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-methylsulfamate (I-132) Step a:[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-vinyl-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl]methyltritylsulfamate

A solution of[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate (1.00 g, 1.54 mmol), (2-ethenyl)tri-n-butyltin (900.0μL, 3.08 mmol), and Pd(PPh₃)₂Cl₂ (55.0 mg, 0.0784 mmol) in1,2-dichloroethane (30.0 mL, degassed with N₂) was heated to refluxunder an atmosphere of nitrogen for 4.5 hours. The reaction wasconcentrated and the residue was purified by flash chromatography (0 to100% EtOAc/hexanes) to yield the product (550 mg, 56%).

LCMS: R.t. 2.06 min ES+ 640 (ammonium acetate).

Step b:[(3aR,4R,6R,6aR)-6-(6-ethyl-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]-dioxol-4-yl]methyltritylsulfamate

A suspension of[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-vinyl-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate (150.0 mg, 0.23 mmol) and Pd/C (10% Pd by weight, 10 mg)in MeOH (3.0 mL, degassed with N₂) was stirred under an atmosphere ofhydrogen for 90 minutes. The suspension was filtered through celite withmethanol and the filtrate was concentrated to yield the crude product(149 mg, 99%).

LCMS: R.t. 1.92 min ES+ 642 (ammonium acetate).

Step c:[(2R,3S,4R,5R)-5-(6-ethyl-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-methylsulfamate (I-132)

A solution of[(3aR,4R,6R,6aR)-6-(6-ethyl-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate (149.0 mg, 023 mmol) in TFA/water (5.0 mL, 9:1) wasstirred for 30 minutes, concentrated to dryness, dissolved in methanoland concentrated again. The residue was purified by prep HPLC to yieldthe title compound (70 mg, 84%).

LCMS: R.t. 0.83 min ES+ 360 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.81 (s, 1H); 8.62 (s, 1H); 6.18 (d, J=5.0Hz, 1H); 4.76 (t, J=5.1 Hz, 1H); 4.47-4.41 (m, 2H); 4.39-4.32 (m, 2H);3.17 (q, J=7.6 Hz, 2H); 1.38 (t, J=7.6 Hz, 3H).

Example 121N-[((2R,3S,4R,5R)-5-{6-[(4-fluorobenzyl)amino]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methyl]sulfamide(I-126)

A solution ofN-{[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide(25.0 mg, 0.0618 mmol), 4-fluorobenzylamine (14.1 μL, 0.124 mmol), andDIPEA (10.8 μL, 0.0618 mmol) in EtOH (0.4 mL) was heated at 100° C. for10 minutes using microwave irradiation. Upon cooling, the mixture wasconcentrated and the residue dissolved in TFA/water (1 mL, 9:1). Thesolution was stirred for 10 minutes, concentrated, taken up in MeOH,then concentrated. The residue was purified by reverse phase HPLC toyield 6.5 mg (23%) of final compound.

LCMS: Rt. 1.28 min ES+ 454 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.32 (s, 1H); 8.16 (s, 1H); 7.43-7.36 (m,2H); 7.07-6.99 (m, 2H); 5.87 (d, J=7.0 Hz, 1H); 4.89 (dd, J=5.5, 7.0 Hz,1H); 4.81-4.75 (m, 2H); 4.36-4.28 (m, 2H); 3.40-3.35 (m, 2H).

Example 122((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-methyl-9H-purin-9-yl)-tetrahydrofuran-2-yl)methylsulfamate (I-104) Step a:[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate

To a solution of((3aR,4R,6R,6aR)-(6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyltritylsulfamate (0.150 g, 0.231 mmol) in THF (2.0 mL) was addedPd(PPh₃)₄ (0.015 g) followed by a solution of MeZnCl in THF (2M, 0.17mL, 0.347 mmol) over 15 min. The reaction was heated at 60° C. for 1 hunder atmosphere of argon. The reaction was cooled to r.t., quenchedwith saturated NH₄Cl and extracted with EtOAc. The combined organicswere washed with saturated aq EDTA.Na₂, water, dried (Na₂SO₄) andconcentrated to give the product (0.28 g) which was used without furtherpurification.

LCMS: R.t=2.00 min, ES+ 628 (ammonium acetate).

Step b:((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-methyl-9H-purin-9-yl)-tetrahydrofuran-2-yl)methylsulfamate (I-104)

The title compound was prepared as described in Example 67 step f, andpurified by preparative HPLC.

LCMS: R.t=0.79 min, ES+ 346 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.80 (s, 1H); 8.67 (s, 1H); 7.60 (bs, 2H);6.06 (d, J=5.2 Hz, 1H); 5.70-5.65 (m, 1H); 5.53-5.47 (m, 1H); 4.70-4.66(m, 1H); 4.32-4.17 (m, 2H); 2.73 (s, 3H).

Example 123{(2R,3S,4R,5R)-5-[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-122) Step a:((3aR,4R,6R,6aR)-6-{6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-9H-purin-9-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyltritylsulfamate

To a suspension of Zn (1.17 g, 17.9 mmol) in DMF (5.0 mL), was addedMe₃SiCl (30.0 μL, 0.237 mmol) and 1,2 dibromoethane (20.0 μL, 0.232mmol). The mixture was stirred at r.t. for 15 min then cooled to 0° C.To this was added N-bromomethylphthalimide (4.30 g, 17.9 mmol) in DMF(20.0 mL) dropwise, the greenish mixture was stirred at r.t overnightthen transferred into a solution of Pd(PPh₃)₄ (0.047 g, 0.040 mmol) and[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purine-9-yl)-2,2-dimethyltetrahyrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate(0.5 g, 0.818 mmol) in DMF (8.0 mL) under argon. The mixture was stirredat r.t. for 2 days. The reaction was concentrated and the residue wasdissolved in DCM, extracted with saturated aq EDTA.Na₂, dried (MgSO₄),filtered and concentrated. The crude product was purified by flashchromatography (20 to 75% EtOAc/hexanes) to afford the title compound(0.243 g, 39%).

LCMS: R.t. 2.13 min ES+ 773 (formic acid)

Step b:{(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl}methyltritylsulfamate

A solution of [(3aR,4R,6R,6aR)-6-{6[(1,3]dioxol1,3-dihdro-2H-isoindol-2yl)-methyl]-9H-purine-9-yl)-2,2-dimethyltetrahyrofuro[3,4-d][1,3]dioxol-4-yl]-methyltritylsulfamate(0.286 g, 0.370 mmol) and hydrazine hydrate (0.20 mL, 3.70 mmol) in EtOH(7.0 mL) was heated at reflux for 45 min. The mixture was cooled to r.t., filtered and concentrated to give the title compound (0.219 g, 92%)which was used without further purification

LCMS: R.t. 1.41 min ES+ 643 (ammonium acetate).

Step c:{(3aR,4R,6R,6aR)-6-[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyltritylsulfamate

A solution of[(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purine-9-yl)-2,2-dimethyltetrahyrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate(0.156 g, 0.243 mmol), o-xylene dibromide (0.065 g, 0.243 mmol), n-Bu₄NI(0.03 g, 0.08 mmol), and Na₂CO₃ (0.052 g, (0.485 mmol) in THF (5.00 mL)was heated at reflux for 3 h. Water (5 mL) was added and the reactionmixture was extracted with ethyl acetate, dried over MgSO₄, andconcentrated. The crude product was purified by flash chromatography (0to 10% MeOH/DCM) to afford the title compound (0.10 g, 76%).

LCMS: R.t. 1.61 min ES+ 745 (ammonium acetate).

Step d:{(2R,3S,4R,5R)-5-[6-(1,3-dihydro-2H-isoindol-2-ylmethyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydrofuran-2-yl}methylsulfamate (I-122)

The title compound was prepared as described in Example 67, step f, andpurified by preparative HPLC.

LCMS: R.t. 0.92 min ES+ 463 (formic acid)

¹H-NMR (300 MHz, CD₃OD): δ 8.90 (s, 1H); 8.70 (s, 1H), 7.29-7.25 (m,4H); 6.22 (d, J=4.9 Hz, 1H); 4.84-4.71 (m, 3H); 4.48-4.34 (m, 8H).

Example 124((2R,3S,4R,5S)-5-(6-((2,3-dihydro-1H-inden-2-yl)methyl)-9H-purin-9-yl)-3,4-dihdrofuran-2-yl)methylsulfamate (I-111) Step a:((3aR,4R,6S,6aR)-6(6-((2,3-dihdro-1H-inden-2-yl)methyl)-9H-purin-9-yl)-2-2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyltrilylsulfamate

To a suspension of Zn (0.184 g, 2.82 mmol) in THF (0.8 mL) under argonwas added Me₃SiCl (4.4 μL, 0.035 mmol) and 1,2-dibromoethane (3.0 μL,0.035 mmol). The mixture was stirred at r.t. for 15 min and then cooledto 0° C. 2-(Iodomethyl)-2,3-dihydro-1H-indene (0.364 g, 1.40 mmol)(Taniguchi, K.; Kuroda, S.; Tsubaki, K.; Shimizu, Y.; Takasugi, H.Preparation of piperidino derivatives which promote growth hormonerelease. WO9851687) in 3.2 mL THF was added dropwise. The greenishsolution was stirred at 40° C. overnight. The resulting mixture wastransferred into a solution of Pd(PPh₃)₄ (0.04 g, 0.035 mmol) and[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purine-9-yl)-2,2-dimethyltetrahyrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate(0.456 g, 0.704 mmol) in THF (3.2 mL) under argon and stirred at 40° C.for 5 h then concentrated. The residue was dissolved in DCM, extractedwith saturated aq EDTA.Na₂, dried (MgSO₄), filtered and concentrated.The crude product was purified by flash chromatography (0 to 5%MeOH/DCM) to afford the title compound (0.098 g, 17%).

LCMS: R.t. 2.77 min ES+ 744 (ammonium acetate).

Step b:((2R,3S,4R,5S)-5-(6-((2,3-dihydro-1H-inden-2-yl)methyl)-9H-purin-9-yl)-3,4-dihdrofuran-2-yl)methylsulfamate (I-111)

The title compound was prepared as described in Example 67, step f, andpurified by preparative HPLC.

LCMS: R.t. 2.19 min; ES+ 446 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.51 (s, 1H); 8.47 (s, 1H), 7.22-7.19 (m,2H); 7.12-7.09 (m, 2H); 6.15 (d, J=4.9 Hz, 1H); 4.74-4.71 (m, 1H);4.64-4.59 (m, 2H); 4.45-4.32 (m, 2H); 3.40-2.85 (m, 7H).

Example 125[(2R,3S,4R,5R)-5-(6-cyclopropyl-9H-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-yl]methylsulfamate (I-114) Step a:[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-vinyl-9H-purin-9-yl)tetrahydrofuro[3,4d][1,3]dioxol-4-yl]methyl acetate

To a solution of[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate (1.24 g, 3.36 mmol) in dichloroethane (20 mL) were addedtributyl(vinyl)stannane (1.50 mL, 5.10 mmol) and Pd(PPh₃)₂Cl₂ (118 mg,0.16 mmol). The r×n mixture was heated at reflux until the startingmaterial was consumed, concentrated, and the residue was purified byflash chromatography (0 to 50% EtOAc/hexanes) to obtain the titlecompound as a viscous oil (1.03 g, 85%).

LCMS: R.t. 1.38 min ES+ 361 (formic acid).

Step b:[(3aR,4R,6R,6aR)-6-(6-cyclopropyl-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d][1,3]dioxol-4-yl]methanol

A suspension of trimethylsulfoxonium iodide (150 mg, 0.68 mmol and NaH(60% in mineral oil, 18 mg, 0.75 mmol) in DMSO (2.00 mL) was stirred for30 minutes at r.t.[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-vinyl-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylacetate (50 mg, 0.13 mmol) in DMSO (3 mL) was added slowly and thereaction was stirred at r.t. for 90 minutes. The reaction mixture wastreated with saturated aq NH₄Cl and extracted with DCM. The combinedorganics were washed with brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 50%EtOAc/hexanes) to yield the title compound (15 mg, 33%).

LCMS: R.t. 1.20 min ES+ 333 (formic acid).

Step c:[(2R,3S,4R,5R)-5-(6-cyclopropyl-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methylsulfamate (I-114)

The title compound was prepared following the procedure described inExample 1, steps c-d.

LCMS: R.t. 1.29 min ES+ 372 (formic acid).

¹H-NMR (400 MHz, CD₃OD): δ 8.68 (s, 1H), 8.57 (s, 1H), 6.16 (d, J=5.0Hz, 1H), 4.73 (t, J=5.0 Hz, 2H), 4.44-4.41 (m, 2H), 4.33-4.32 (m, 1H),2.76-2.69 (m, 1H), 1.39-1.35 (m, 2H), 1.27-1.23 (m, 2H).

Example 126(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methoxyethyl)-9H-purin-9-yl]tetrahydro-furan-2-yl}methylsulfamate (I-137) Step a:9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine

To a solution of[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol(2.00 g, 6.12 mmol) and imidazole (0.83 g, 12.24 mmol) in DMF (40 mL) at0° C. was added TBSCl in DMF (10 mL) dropwise. The solution was stirredfor 30 minutes at 0° C. and r.t. for 2 h. The reaction was concentratedand the residue was diluted with DCM and washed with water. The organiclayer was dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (0 to 30% EtOAc/hexanes) to yield thetitle compound (1.82 g, 68%).

Step b:9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-vinyl-9H-purine

To a solution of9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine(330 mg, 0.74 mmol) and tributyl(vinyl)stannane (0.26 mL, 0.88 mmol) in1,2 dichloroethane (10 mL) was added Pd(Ph₃P)₂Cl₂ (26 mg, 0.03 mmol) andthe r×n mixture was heated at reflux overnight. The solvent was removedand the residue purified by flash chromatography (0 to 20%EtOAc/hexanes) to yield 215 mg (67%) of the title compound.

LCMS: R.t. 2.31 min ES+ 434 (formic acid).

Step c:9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-(2-methoxyethyl)-9H-purine

To a stirred solution of9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-vinyl-9H-purine(100 mg, 0.23 mmol) in DCM (5.0 mL) was added NaOMe (0.5M in MeOH, 4.6mL, 2.2 mmol) at 0° C. The reaction was stirred for 2 h at 0° C. andr.t. overnight. The mixture was diluted with DCM and washed withsaturated aq NH₄Cl. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 10%MeOH/DCM) to yield 70 mg (66%) of the title compound.

LCMS: R.t. 2.11 min ES+ 466 (formic acid).

Step d:{(3aR,4R,6R,6aR)-6-[6-(2-methoxyethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxol-4-yl}methanol

To a solution of9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-(2-methoxyethyl)-9H-purine(70 mg, 0.15 mmol) in THF/pyridine (1.5 mL, 1:1) was added hydrofluoricacid in pyridine (15 drops). The reaction was stirred overnight,quenched with saturated aq NaHCO₃, extracted with EtOAc, dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography (0 to 50% DCM/EtOAc to furnish 37 mg (70%) of the titlecompound.

LCMS: R.t. 1.12 min ES+ 351 (formic acid).

Step e:2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methoxyethyl)-9H-purin-9-yl]tetrahydro-furan-2-yl}methylsulfamate (I-137)

The title compound was prepared following the procedure described inExample 1, steps c-d.

LCMS: R.t. 1.11 min ES+ 390 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.84 (s, 1H); 8.67 (s, 1H); 6.05 (d, J=5.5Hz, 1H); 4.68 (t, J=5.3 Hz, 2H); 4.31-4.17 (m, 4H); 3.88 (t, J=6.5 Hz,2H); 3.33 (t, J=6.5 Hz, 2H); 3.15 (s, 3H).

Example 127(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(pyridin-3-ylcarbonyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-105) Step a:[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-{[(pyridin-3-ylcarbonyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate

To a solution of{(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyltritylsulfamate (145 mg, 0.22) and DIPEA (0.08 mL, 0.48 mmol) at 0° C.in DCM (5.0 mL) was added nicotinoyl chloride (64 mg, 0.36 mmol). Afterone hour, the reaction was quenched with saturated aq NH₄Cl andextracted with DCM. The combined organics were dried (Na₂SO₄), filteredand concentrated. The residue was purified by flash chromatography (0 to10% MeOH/DCM to furnish the title compound (65 mg, 40%).

LCMS: R.t. 86 min ES+ 748 (formic acid).

Step b:(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(pyridin-3-ylcarbonyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-105)

The title compound was prepared following the procedure described inExample 1 step d.

LCMS: R.t. 1.05 min ES+ 466 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 9.08-9.07 (m, 1H); 8.87 (s, 1H); 8.7-8.66 (m,1H); 8.63 (s, 1H); 8.35-8.31 (m, 1H); 7.58-7.53 (m, 1H); 6.21 (d, J=4.9Hz, 1H); 5.11 (s, 2H); 4.75 (t, J=5.0 Hz, 1H); 4.45-4.32 (m, 4H).

Example 128(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(2-methoxybenzoyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-116) Step a:[(3aR,4R,6R,6aR)-6-(6-{[(2-methoxybenzoyl)amino]methyl}-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate

The title compound was prepared following the procedure described inExample 127, step a using{(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyltritylsulfamate and 2-methoxybenzoyl chloride.

LCMS: R.t. 2.14 min ES+ 777 (formic acid).

Step b:(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-{[(2-methoxybenzoyl)amino]methyl}-9H-purin-9-yl)tetrahydrofuran-2-yl]methylsulfamate (I-116)

The title compound was prepared following the procedure described inExample 1 step d.

LCMS: R. t. 1.16 min ES+ 495 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.92 (s, 1H); 8.75 (s, 1H); 7.93-7.9 (m,1H); 7.54-7.48 (m, 2H); 7.14 (d, 1H); 7.06 (t, J=7.2 Hz, 1H); 6.10 (d,J=5.2 Hz, 1H); 5.74-5.52 (m, 2H); 5.03-5.02 (m, 2H); 4.71-4.67 (m, 1H);4.28-4.20 (m, 4H); 3.99 (s, 3H).

Example 129(2R,3S,4R,5R)-5-(6-{[(3,5-difluorobenzoyl)amino]methyl}-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methylsulfamate (I-125) Step a:[(3aR,4R,6R,6aR)-6-(4[(3aR,4R,6R,6aR)-6-(6-{[(3,5-difluorobenzoyl)amino]methyl}-a.9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamate

The title compound was prepared following the procedure described inExample 127, step a using{(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyltritylsulfamate and 3,5-difluorobenzoyl chloride.

LCMS: R.t 2.14 min ES+ 783 (formic acid).

Step b:(2R,3S,4R,5R)-5-(6-{[(3,5-difluorobenzoyl)amino]methyl}-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methylsulfamate (I-125)

The title compound was prepared following the procedure described inExample 1 step d.

LCMS: R.t. 1.23 min ES+ 501 (formic acid).

¹H-NMR (300 MHz, CD₃OD): δ 8.88 (s, 1H); 8.65 (s, 1H); 7.54-7.51 (m,2H); 7.21-7.14 (m, 1H); 6.21 (d, J=4.9 Hz, 1H); 5.08 (s, 2H); 4.75 (t,J=5.0 Hz, 1H); 4.45-4.32 (m, 4H).

Example 130((2R,3S,4R,5R)-5-{6-[(benzoylamino)methyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-129)

The title compound was prepared as described in Example 127 steps a-b,using benzoyl chloride in step a and purified by preparative HPLC.

LCMS: R.t=0.97 min, ES+ 465 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 9.18 (t, J=6.1 Hz, 1H); 8.88 (s, 1H); 8.73(s, 1H); 7.92 (d, J=7.5 Hz, 2H); 7.61-7.46 (m, 5H); 6.09 (d, J=5.5 Hz,1H); 5.73 (d, J=5.8 Hz, 1H); 5.53 (d, J=3.3 Hz, 1H); 4.93 (d, J=5.5 Hz,2H); 4.70 (q, J=5.2 Hz, 1H), 4.32-4.17 (m, 4H).

Example 131((2R,3S,4R,5R)-5-{6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-9H-purin-9-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-120)

The title compound was prepared as described in Example 67, step f,using [(3aR,4R,6R,6aR)-6-{6[(1,3]dioxol1,3-dihdro-2H-isoindol-2-yl)-methyl]-9H-purine-9-yl)-2,2-dimethyltetrahyrofuro[3,4-d][1,3]dioxol-4-yl]methyltritylsulfamateand purified by preparative HPLC.

LCMS: R.t=1.21 min, ES+ 491 (formic acid).

¹H-NMR (400 MHz, d₆-DMSO): δ 8.84 (s, 1H); 8.69 (s, 1H); 7.97-7.89 (m,4H); 7.58 (bs, 2H); 6.06 (d, J=5.3 Hz, 1H); 5.72 (d, J=5.5H, 1 Hz); 5.51(d, J=5.3 Hz, 1H); 5.28 (s, 2H); 4.67 (q, J=5.5, 10.5 Hz, 1H); 4.30-4.16(m, 4H).

Example 132{(2R,3S,5R)-3-Hydroxy-5-[5-iodo-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-2-yl}methylsulfamate (I-117) Step a: 5-Iodo-4-phenethyl-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 4-phenethyl-7H-pyrrolo[2,3-d]pyrimidine (3.15 g, 14.1mmol) in AcCN was added N-iodosuccinimide and the mixture was stirred atr.t. for 12 hr. The precipitate was collected and recrystallized fromMeOH to give the title compound (4.06 g, 83%).

LCMS: R.t. 1.59 min ES+ 350 (ammonium acetate).

Step b:{(2R,3S,5R)-3-Hydroxy-5-[5-iodo-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-2-yl}methylsulfamate (I-117)

The title compound was prepared following the procedure described inExample 91, steps a-e, using TBSCl instead of TIPSCl in step c, andusing 5-iodo-4-phenethyl-7H-pyrrolo-[2,3-d]pyrimidine in step a.

LCMS: R.t. 7.15 min (15 min run) ES+ 545 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.70 (s, 1H); 7.88 (s, 1H); 7.30-7.35 (m,2H); 7.23-7.28 (m, 2H); 7.15-7.19 (m, 1H); 6.78 (dd, J=6.3, 8.0 Hz, 1H);4.60-4.56 (m, 1H); 4.31-4.29 (m, 2H); 4.20-4.17 (m, 1H); 3.61-3.57 (m,2H); 3.10-3.02 (m, 2H); 2.66-2.60 (m, 1H); 2.43-2.37 (m, 1H).

Example 133{(2R,3S,5R)-5-[5-Ethynyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-135) Step a:(2R,3S,5R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-5-{4-(2-phenylethyl)-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydrofuran-3-ylacetate

To a suspension of(2R,3S,5R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(5-iodo-4-phenethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofuran-3-ylacetate 9 obtained from example 132, step d) (0.36 g, 0.578 mmol), CuI(0.022 g, 0.0116 mmol), Pd(PPh₃)₂Cl₂ (0.040 g, 0.0570 mmol) and DIPEA(0.20 mL, 1.15 mmol) in DMF was added ethynyltrimethylsilane (0.230 g,2.34 mmol). The mixture was stirred at r.t. for 12 h. The reactionmixture was diluted with EtOAc. The organic layer was washed with H₂O,dried (MgSO₄), filtered, and concentrated. The residue was purified byflash chromatography (0 to 25% EtOAc/hexanes) to give the title compound(0.305 g, 58%).

LCMS: R.t. 2.96 min ES+ 592 (ammonium acetate).

Step b:(2R,3S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{4-(2-phenylethyl)-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydrofuran-3-ylacetate

The title compound was prepared following the procedure described inExample 40, steps e-f.

LCMS: R.t. 2.12 min ES+ 557 (ammonium acetate).

Step c:{(2R,3S,5R)-5-[5-Ethynyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-135)

To a solution of(2R,3S,5R)-2-{[(aminosulfonyl)oxy]methyl}-5-{4-(2-phenylethyl)-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}tetrahydrofuran-3-ylacetate (0.254 g, 0.457 mmol) in MeOH (5 mL) at r.t. was added K₂CO₃(0.168 g, 1.22 mmol) and the mixture was stirred for 2 h. The reactionmixture was diluted with CH₂Cl₂, washed with saturated aq NaHCO₃, driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (0 to 10% MeOH/DCM) to give the title compound(0.126 g, 62%).

LCMS: R.t. 1.51 min ES+ 433 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.71 (s, 1H); 7.95 (s, 1H); 7.34-7.22 (m,4H); 7.20-7.13 (m, 1H); 6.77 (dd, J=8.0, 6.3 Hz, 1H); 4.61-4.56 (m, 1H);4.33-4.29 (m, 2H); 4.21-4.17 (m, 1H); 3.77 (s, 1H); 3.59-3.54 (m, 2H);3.10-3.06 (m, 2H); 2.67-2.60 (m, 1H); 2.45-2.44 (m, 1H).

Example 134{(2R,3S,5R)-5-[5-Ethyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-124)

A suspension of{(2R,3S,5R)-5-[5-ethynyl-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (0.0824 g, 0.190 mmol) and Pd/C (10% wt, ˜50% H₂O, 0.01 g) inEtOH (10 mL) was stirred under an atmosphere of H₂ (1 atm) for 5 h atr.t. The reaction mixture was filtered through celite and the filtratewas concentrated. The residue was purified by flash chromatography (0 to10% MeOH/DCM) to give the title compound (0.010 g, 11%).

LCMS: R.t. 7.70 min (15 min run) ES+ 447 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): δ 8.65 (s, 1H); 7.43 (s, 1H); 7.26-7.12 (m,5H); 6.81 (dd, J=8.3, 6.3 Hz, 1H); 4.58-4.56 (m, 1H); 4.30-4.29 (m, 2H);4.19-4.16 (m, 1H); 3.37-3.33 (m, 2H); 3.10-3.05 (m, 2H); 2.85-2.78 (m,2H); 2.65-2.59 (m, 1H); 2.38-2.32 (m, 1H); 1.31 (t, J=7.5 Hz, 3H).

Example 135{(2R,3S,5R)-5-[5-[3-(Diethylamino)prop-1-yn-1-yl]-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-131) Step a:(2R,3S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-[5-[3-(diethylamino)prop-1-yn-1-yl]-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3-ylacetate

The title compound was prepared following the procedure described inExample 133, step a using N,N-diethylprop-2-yn-1-amine.

LCMS: R.t. 1.56 min ES+ 570 (ammonium acetate)

Step b:{(2R,3S,5R)-5-[5-[3-(Diethylamino)prop-1-yn-1-yl]-4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-hydroxytetrahydrofuran-2-yl}methylsulfamate (I-131)

The title compound was prepared following the procedure described inExample 40, step g and purified by HPLC.

LCMS: R.t. 1.60 min ES+ 528 (ammonium acetate).

¹H-NMR (400 MHz, CD₃OD): 8.74 (s, 1H); 8.02 (s, 1H); 7.31-7.22 (m, 4H);7.20-7.15 (m, 1H); 6.79 (dd, J=7.8, 6.3 Hz, 1H); 4.59-4.56 (m, 1H);4.32-4.30 (m, 2H); 4.22-4.20 (m, 1H); 3.93 (s, 2H); 3.62-3.55 (m, 2H);3.16-3.10 (m, 2H); 2.94-2.82 (m, 4H); 2.63-2.57 (m, 1H); 2.47-2.39 (m,1H); and 1.14 (t, J=7.0 Hz, 6H).

Example 136((2R,3S,4R,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-c]pyridin-1-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-149) Step a: 4-amino-2-chloro-3-nitropyridine

To a solution of 4-amino-2-chloropyridine (10.0 g, 77.8 mmol) inconcentrated H₂SO₄ (60 mL) at 0° C. was added 90% nitric acid (30 mL)dropwise. The solution was stirred at 0-5° C. for 30 min then pouredonto ice (carefully). The pH was brought to ˜3 with concentrated aqammonium hydroxide (˜150 mL) to obtain a white precipitate which wasisolated and dried by filtration. The white solid was dissolved insulfuric acid (100 mL), heated at 80° C. for 5 h, stirred at r.t.overnight, then poured on crushed ice. At 0° C. the pH was adjusted to˜3 with concentrated aq ammonium hydroxide (˜250 mL) to obtain a yellowprecipitate which was isolated by filtration. The solid was dried undervacuum overnight to obtain ˜13 g of a mixture of 3- and 5-nitro isomers.A sample (4.0 g) was purified by flash chromatography (0 to 20%DCM/EtOAc) to obtain 1.77 g of the product as a fluffy yellow solid.

LCMS: R.t 1.15 min, ES+ 174 (formic acid).

Step b:N(2)-1-[(1S)-2,3-dihydro-1H-inden-1-yl]-3-nitropyridine-2,4-diamine

4-amino-2-chloro-3-nitropyridine (1.67 g, 9.6 mmol),(S)-(+)-1-aminoindan (1.85 mL, 14.4 mmol) and triethylamine (2.68 mL,19.2 mmol) were refluxed in EtOH (20 mL) for 14 h. The reaction wasconcentrated and the residue was purified by flash chromatography (0 to25% DCM/EtOAc) to obtain the product (2.59 g, 72%) as a yellow solid.

LCMS: R.t=1.16 min, ES+ 271 (formic acid).

Step c: N(2)-[(1S)-2,3-dihydro-1H-inden-1-yl]pyridine-2,3,4-triamine

To a suspension ofN(2)-[(1S)-2,3-dihydro-1H-inden-1-yl]-3-nitropyridine-2,4-diamine (1.042g, 3.9 mmol) and iron (1.29 g, 23.1 mmol) in i-PrOH/water (40 mL, 3:1)was added concentrated hydrochloric acid (400 μL). The reaction washeated at 60° C. for 2 h and filtered through a pad of celite. Thefiltrate was concentrated to dryness to obtain the product as a greysolid (1.0 g, quantitative) which was used without further purification.

LCMS: R.t=0.90 min, ES+ 241 (formic acid).

Step d:N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1H-imidazo[4,5-c]pyridin-4-amine

To a suspension ofN(2)-[(1S)-2,3-dihydro-1H-inden-1-yl]pyridine-2,3,4-triamine (1.0 g, 4.2mmol) in ethyl orthoformate (20 mL) was added conc. hydrochloric acid(1.0 mL). The reaction was stirred for 14 h, the solution wasconcentrated and the residue was purified by flash chromatography (1 to10% MeOH/DCM) to obtain the product as a brown solid (947 mg, 91%).

LCMS: R.t=0.89 min, ES+ 251 (formic acid).

Step e:(2R,3R,4R,5R)-2-[(benzoyloxy)methyl]-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-c]pyridin-1-yl}tetrahydrofuran-3,4-diyldibenzoate

To a solution ofN-[(1S)-2,3-dihydro-1H-inden-1-yl]-1H-imidazo[4,5-c]pyridin-4-amine (160mg, 0.64 mmol) in AcCN (5 mL) was added N,O-bis(trimethylsilyl)acetamide (474 μL, 1.92 mmol) dropwise to obtain aclear solution which was refluxed for 10 min. The solution was allowedto cool to r.t and 1-O-acetyl-2,3,5-tri-O-benzoyl-8-D-ribofuranose (322mg, 0.64 mmol) was added as a solution in AcCN (3 mL). Trimethylsilyltrifluoromethanesulfonate (115 μL, 0.64 mmol) was added dropwise and thereaction was heated at reflux for 3 h. The reaction was quenched withMeOH, concentrated, and the residue was purified by flash chromatography(0 to 25% DCM/EtOAc) to obtain the product as a white solid (266 mg,60%).

LCMS: R.t=1.63 min, ES+ 695 (formic acid).

Step f:((3aR,4R,6R,6aR)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-c]-pyridin-1-yl}-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol

A solution of(2R,3R,4R,5R)-2-[(benzoyloxy)methyl]-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-c]pyridin-1-yl}tetrahydrofuran-3,4-diyldibenzoate (250 mg, 0.36 mmol) in 7 M ammonia in methanol (15 mL) wasstirred for 16 h. The reaction was concentrated and the residuedissolved in acetone (5 mL). To this was added p-toluenesulfonic acidmonohydrate (70 mg, 0.4 mmol) and 2,2-dimethoxypropane (500 μL, 4 mmol)and the reaction was stirred for 16 h. To this was added 0.5M aq NaHCO₃(20 mL) and the volume was reduced in vacuo. The aq residue wasextracted with CHCl₃ (3×), the combined organics were dried (Na₂SO₄),filtered, and concentrated. The residue was purified by flashchromatography (25 to 100% DCM/EtOAc) to obtain the product as a whitepowder (94 mg, 62%).

LCMS: R.t=1.05 min, ES+ 423 (formic acid).

Step g:((2R,3S,4R,5R)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1H-imidazo[4,5-c]pyridin-1-yl}-3,4-dihydroxytetrahydrofuran-2-yl)methylsulfamate (I-149)

The title compound was prepared following the procedure described inExample 67, steps e-f and purified by HPLC.

LCMS: R.t=0.91 min, ES+ 462 (formic acid).

¹H-NMR (300 MHz, d₆-DMSO): δ 8.25 (s, 1H); 8.16 (s, 1H); 7.80 (d, J=5.8Hz, 1H); 7.66 (s, 2H); 7.26-7.08 (m, 4H); 6.92 (d, J=5.8 Hz, 1H); 6.76(d, J=8.6 Hz, 1H); 5.90 (dd, J=16.2, 8.3 Hz, 1H); 5.83 (d, J=6.2 Hz);4.37 (dd, 1H, J=5.9, 5.9 Hz); 4.29-4.10 (m, 4H); 2.99 (m, 1H); 2.83 (m,1H); 2.47 (m, 1H); 2.07 (m, 1H).

Example 137{(2R,3S,5R)-3-methoxy-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}methylsulfamate (I-151) Step a: 4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine

Phenethyl magnesium bromide (0.5 M solution in THF, 12 mL, 6.15 mmol)was added dropwise to a stirred solution of4-chloro-7Hpyrrolo[2,3-d]pyrimidine (0.210 g, 1.37 mmol) and Fe(acac)₃(0.1 g 0.273 mmol) in THF (5.0 mL) under Ar. The resulting reactionmixture was stirred at r.t. for 8 h. The mixture was poured onto amixture of ice (10 mL) and NH₄Cl (0.5 g) and the product was extractedwith CHCl₃. The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by flash chromatography (0to 10% MeOH/DCM) to afford the title compound (0.166 g, 54%).

LCMS: R.t. 1.50 min ES+ 224 (ammonium acetate).

Step b:(2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydrofuran-3-ol

The title compound was prepared following the procedure described inExample 91 steps a-c using 4-(2-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidinein step a and TBSCl instead of TIPSCl in step c.

LCMS: R.t. 2.06 min ES+ 455 (formic acid).

Step c:9-[(2R,4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxytetrahydro-furan-2-yl]-6-(2-phenylethyl)-9H-purine

To a solution of(2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydrofuran-3-ol(98 mg, 0.22 mmol) in THF (1.5 mL) at 0° C. was added NaH (60% in oil,13 mg, 0.33 mmol) and the suspension stirred for 10 minutes. MeI (26 μL,0.26 mmol) was added dropwise and the reaction was warmed to roomtemperature. After one hour the reaction was quenched with saturated aqNH₄Cl, partitioned between brine and EtOAc, separated, and the aq layerwas extracted with EtOAc (5×). The combined organics were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by flash chromatography (20 to 50% EtOAc/hexanes) to give thetitle compound (67 mg, 65%).

LCMS: R.t. 2.39 min ES+ 469 (formic acid).

Step d:{(2R,3S,5R)-3-methoxy-5-[6-(2-phenylethyl)-9H-purin-9-yl]tetrahydrofuran-2-yl}-methylsulfamate (I-151)

The title compound was prepared following the procedure described inExample 40 steps e-f.

LCMS: R.t. 1.28 min ES+ 434 (formic acid).

¹H-NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H); 8.27 (s, 1H); 7.25-7.16 (m, 5H);6.44 (dd, J=6.2, 7.8 Hz, 1H); 5.82 (s, 2H); 4.40 (m, 3H); 4.21 (m, 1H);3.43 (dd, J=7.8, 10.5 Hz, 2H); 3.38 (s, 3H); 3.17 (dd, J=5.8, 8.5 Hz,2H); 2.82 (ddd, J=6.0, 7.9, 13.7 Hz, 1H); 2.57 (ddd, J=2.8, 6.2, 9.0 Hz,1H).

Example 138 Enzyme Preparation

All protein accession numbers provided herein refer to the EntrezProtein database maintained by the National Center for BiotechnologyInformation (NCBI), Bethesda, Md.

Generation of E1 Enzymes

Following manufacturer instructions, baculoviruses were generated withthe Bac-to-Bac Expression System (Invitrogen) for the followingproteins: untagged NAEα (APPBP1; NP_(—)003896.1), N-terminallyHis-tagged NAEβ (UBE1C; NP_(—)003959.3), untagged SAEα (SAE1;NP_(—)005491.1), N-terminally His-tagged SAEβ (UBA2; NP_(—)005490.1),N-terminally His-tagged murine UAE (UBE1X; NP_(—)033483). NAEα/His-NAEβand SAEα/His-SAEβ complexes were generated by co-infection of Sf9 cells,which were harvested after 48 hours. His-mUAE was generated by singleinfection of Sf9 cells and harvested after 72 hours. Expressed proteinswere purified by affinity chromatography (Ni-NTA agarose, Qiagen) usingstandard buffers.

Generation of E2 Enzymes

Ubc12 (UBE2M; NP_(—)003960.1), Ubc9 (UBE2I; NP_(—)003336.1), Ubc2(UBE2A; NP_(—)003327.2) were subcloned into pGEX (Pharmacia) andexpressed as N-terminally GST tagged fusion proteins in E. coli.Expressed proteins were purified by conventional affinity chromatographyusing standard buffers.

Generation of Ubl Proteins

Nedd8 (NP_(—)006147), Sumo-1 (NP_(—)003343) and Ubiquitin (withoptimized codons) were subcloned into pFLAG-2 (Sigma) and expressed asN-terminally Flag tagged fusion proteins in E. coli. Expressed proteinswere purified by conventional chromatography using standard buffers.

Example 139 E1 Enzyme Assays Nedd8-Activating Enzyme (NAE) HTRF Assay

The NAE enzymatic reaction totaled 50 μL and contained 50 mM HEPES (pH7.5), 0.05% BSA, 5 mM MgCl₂, 20 μM ATP, 250 μM GSH, 0.01 μM Ubc12-GST,0.075 Nedd8-Flag and 0.28 nM recombinant human NAE enzyme. The enzymaticreaction mixture, with and without compound inhibitor, was incubated at24° C. for 90 minutes in a 384-well plate before termination with 25 μLof Stop/Detection buffer (0.1M HEPES pH 7.5, 0.05% Tween20, 20 mM EDTA,410 mM KF, 0.53 nM Europium-Cryptate labeled monoclonal anti-FLAG M2antibody (CisBio International) and 8.125 μg/mL PHYCOLINK goat anti-GSTallophycocyanin (XL-APC) antibody (Prozyme)). After incubation for 3hours at 24° C., quantification of the FRET was performed on theAnalyst™ HT 96.384 (Molecular Devices).

Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12,I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-21, I-22, I-23, I-24, I-25,I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37,I-38, I-39, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-50, I-51,I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64,I-65, I-66, I-67, I-68, I-69, I-71, I-79, I-87, I-88, I-90, I-91, I-92,I-94, I-95, I-96, I-97, I-98, I-100, I-101, I-102, I-103, I-104, I-105,I-107, I-108, I-109, I-110, I-111, I-112, I-113, I-114, I-115, I-116,I-118, I-119, I-120, I-121, I-122, I-123, I-124, I-125, I-126, I-127,I-128, I-129, I-130, I-132, I-134, I-135, I-136, I-137, I-138, I-139,I-140, I-141, I-143, I-144, I-145, I-146, I-147, I-148, I-149, I-150,and I-152 exhibited IC₅₀ values less than or equal to 1 μM in thisassay.

Compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12,I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-21, I-22, I-23, I-24, I-25,I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-37, I-39, I-42, I-43,I-45, I-46, I-47, I-48, I-50, I-51, I-53, I-54, I-55, I-56, I-57, I-58,I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-71,I-79, I-87, I-88, I-90, I-91, I-92, I-94, I-95, I-96, I-100, I-101,I-102, I-103, I-104, I-105, I-107, I-108, I-109, I-110, I-111, I-112,I-113, I-114, I-115, I-116, I-118, I-119, I-120, I-121, I-122, I-123,I-125, I-126, I-127, I-128, I-129, I-130, I-132, I-134, I-136, I-137,I-138, I-139, I-140, I-141, I-145, I-146, I-147, I-148, I-149, I-150,and I-152 exhibited IC₅₀ values less than or equal to 100 nM in thisassay.

Sumo-Activating Enzyme (SAE) HTRF Assay.

The SAE enzymatic reaction was conducted as outlined above for NAEexcept that Ubc12-GST and Nedd8-Flag were replaced by 0.01 μM Ubc9-GSTand 0.125 μM Sumo-Flag respectively and the concentration of ATP was 0.5μM. Recombinant human SAE (0.11 nM) was the source of enzyme.

Ubiquitin-Activating Enzyme (UAE) HTRF Assay.

The UAE enzymatic reaction was conducted as outlined above for NAEexcept that Ubc12-GST and Nedd8-Flag were replaced by 0.005 μM Ubc2-GSTand 0.125 μM Ubiquitin-Flag respectively and the concentration of ATPwas 0.1 μM. Recombinant mouse UAE (0.3 nM) was the source of enzyme.

Example 140 Cellular Assays

Anti-Proliferation Assay (WST)

Calu-6 (2400/well) or other tumor cells in 80 μL of appropriate cellculture medium (MEM for Calu6, Invitrogen) supplemented with 10% fetalbovine serum (Invitrogen) was seeded in wells of a 96-well cell cultureplate and incubated for 24 hours in a tissue culture incubator. Compoundinhibitors were added in 20 μL culture media to the wells and the plateswas incubated for 72 hours at 37° C. 10% final concentration of WST-1reagent (Roche) was added to each well and incubated for 3.5 hours (forCalu6) at 37° C. The optical density for each well was read at 450 nmusing a spectrophotometer (Molecular Devices). Percent inhibition wascalculated using the values from a DMSO control set to 100% viability.

Anti-Proliferation Assay (ATPLite)

Calu-6 (1500 cells/well) or other tumor cells were seeded in 72 μL ofappropriate cell culture medium (MEM for Calu6, Invitrogen) supplementedwith 10% fetal bovine serum (Invitrogen) in wells of a 384-wellPoly-D-Lysine coated cell culture plate. Compound inhibitors were addedin 8 μL 10% DMSO/PBS to the wells and the plates were incubated for 72hours at 37° C. Cell culture medium was aspirated, leaving 25 pt in eachwell. 25 μL of ATPlite 1step™ reagent (Perkin Elmer) was added to eachwell. The luminescence for each well was read using the LeadSeekerMicroplate Reader (Molecular Devices). Percent inhibition was calculatedusing the values from a DMSO control set to 100% viability.

Example 141 In Vivo Assays

In Vivo Tumor Efficacy Model

Calu6 (5×10⁶ cells), HCT116 (2×10⁶ cells) or other tumor cells in 100 μLphosphate buffered saline were aseptically injected into thesubcutaneous space in the right dorsal flank of female Ncr nude mice(age 5-8 weeks, Charles River) using a 26-gauge needle. Beginning on day7 after inoculation, tumors were measured twice weekly using a verniercaliper. Tumor volumes were calculated using standard procedures(0.5×(length×width²)). When the tumors reached a volume of approximately200 mm³ mice were randomized into groups and injected intravenously inthe tail vein with compound inhibitor (100 μL) at various doses andschedules. Alternatively, compound inhibitor may be delivered to mice byintraperitoneal or subcutaneous injection or oral administration. Allcontrol groups received vehicle alone. Tumor size and body weight wasmeasured twice a week and the study terminated when the control tumorsreached approximately 2000 mm³.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

While a number of embodiments of this invention have been described, itis apparent that the provided basic examples may be altered to conveyother embodiments, which utilize the compounds and methods of thisinvention. It will thus be appreciated that the scope of this inventionhas been represented herein by way of example and is not intended to belimited by the specific embodiments, rather is defined by the appendedclaims.

1. A compound of formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein: Ring A isselected from the group consisting of:

wherein one ring nitrogen atom in Ring A optionally is oxidized; X is—CH₂—, —CHF—, —CF₂—, —NH—, or —O—; Y is —O—, —S—, or —C(R^(m))(R^(n))—;each R^(h) independently is hydrogen, halo, —CN, —OH, —O—(C₁₋₄aliphatic), —NH₂, —NH—(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —SH,—S—(C₁₋₄ aliphatic), or an optionally substituted C₁₋₄ aliphatic group;R^(j) is hydrogen, —OR⁵, —SR⁶, —N(R⁴)₂, or an optionally substitutedaliphatic, aryl, or heteroaryl group; R^(k) is hydrogen, halo, —OR⁵,—SR⁶, —N(R⁴)₂, or an optionally substituted C₁₋₄ aliphatic group; R^(m)is hydrogen, fluoro, —N(R⁴)₂, or an optionally substituted C₁₋₄aliphatic group, and R^(n) is hydrogen, fluoro, or an optionallysubstituted C₁₋₄ aliphatic group, or R^(m) and R^(n) together form ═O or═C(R⁵)₂; R¹ is hydrogen, chloro, bromo, fluoro, iodo, —NR⁷R⁸, —R⁹, —SH,—SCH₃, —OH, —OCH₃, or —O—R¹¹; R² is hydrogen, chloro, bromo, fluoro,iodo, —N(R⁶)₂, —CN, —O—(C₁₋₄ aliphatic), —OH, —SR⁶, or an optionallysubstituted C₁₋₄ aliphatic group; R^(3a) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, hydroxy, —OR²¹, —NH₂,—NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹, —CON(H)R²¹, —C(O)R⁵, —OC(O)N(H)R²¹,—OC(O)R²¹, —OC(O)OR²¹,) OC(O)OR²¹, —C₁₋₄ fluoroaliphatic, or a —C₁₋₄aliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); R^(3b) isselected from the group consisting of hydrogen, fluoro, C₁₋₄ aliphatic,and C₁₋₄ fluoroaliphatic; R^(3c) is selected from the group consistingof hydrogen, fluoro, —CN, —N₃, hydroxy, —OR²¹, —NH₂, —NH(R²¹),—N(H)CO₂R²¹, —N(H)C(O)R²¹, —CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹,—OC(O)OR²¹, —C₁₋₄ fluoroaliphatic, or a —C₁₋₄ aliphatic optionallysubstituted with one or two substituents independently selected from thegroup consisting of —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); R^(3d) is selected from the group consisting ofhydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic; each R⁴ isindependently hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;or two R⁴, taken together with the carbon atom to which they areattached, form a 3- to 6-membered carbocyclic ring; or one R⁴, takentogether with R⁵ and the intervening carbon atoms, forms a 3- to6-membered spirocyclic ring; or two R⁴ together form ═O; R⁵ is hydrogen,or C₁₋₄ aliphatic; or R⁵, taken together with one R⁴ and the interveningcarbon atoms, forms a 3- to 6-membered spirocyclic ring; R^(5′) ishydrogen, or C₁₋₄ aliphatic; each R⁶ is independently hydrogen or C₁₋₄aliphatic; R⁷ is an optionally substituted C₁₋₁₀ aliphatic, aryl,heteroaryl, or heterocyclyl group; R⁸ is hydrogen or C₁₋₄ aliphatic; R⁹is —V—Z—R^(12a), —V—Z—R^(12b), —R^(12c) or an optionally substitutedaliphatic, aryl, heterocyclyl, or heteroaryl group, wherein theheteroaryl group is attached at a carbon atom; R¹⁰ is an unsubstitutedC₂₋₁₀ aliphatic, a substituted C₁₋₁₀ aliphatic, or an optionallysubstituted aryl, heteroaryl, or heterocyclyl; R¹¹ is an unsubstitutedC₂₋₁₀ aliphatic, a substituted C₁₋₁₀ aliphatic, or an optionallysubstituted aryl, heteroaryl, or heterocyclyl; R^(4x) is hydrogen, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion ofwhich may be optionally substituted; R^(4y) is hydrogen, C₁₋₄ alkyl,C₁₋₄ fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted, or an optionally substituted 5- or 6-memberedaryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y), takentogether with the nitrogen atom to which they are attached, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; each R^(5x) independently is hydrogen, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl orC₆₋₁₀ ar(C₁₋₄)alkyl; V is —S(O)₂—, —S(O)—, —C(O)O—, —C(O)—, —C(NR¹³)═N—,—C(═N(R¹³))-N(R¹³)—, —C(OR¹¹)═N—, —CON(R¹³)—, —N(R¹³)C(O)—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂—, —N(R¹³)SO₂—N(R¹³)—, —N(R¹³)CO₂—,—SO₂N(R¹³)—, —OC(O)—, —OC(O)O—, —OC(O)N(R¹³)—, —N(R¹³)—N(R¹³)—; Z is anoptionally substituted C₁₋₆ alkylene chain, wherein the alkylene chainis optionally interrupted by —C(R¹³)═C(R¹³)—, —C≡C—, —O—, —S—, —N(R¹³)—,—N(R¹³)CO—, —N(R¹³)CO₂—, —C(O)N(R¹³)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —N(R¹³)C(O)N(R¹³)—, —N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—,—S(O)—, —S(O)₂—, —N(R¹³)S(O)₂—, —S(O)₂N(R¹³)—; R^(12a) is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group;R^(12b) is halo, —NO₂, —CN, —OR¹⁴, —SR¹⁵, —N(R¹⁶)₂, —N(R¹⁶)C(O)R¹⁵,—N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)CO₂R¹⁴, —O—CO₂—R¹⁴, —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴,—N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)—OR¹⁵, —N(R¹⁶)S(O)₂R¹⁵, or —N(R¹⁶)SO₂—N(R¹⁶)₂,—C(R¹⁴)═C(R¹⁴)₂, —C(O)R¹⁴, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂,—C(R¹⁴)═N—OR¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, or —C(═NR¹⁶)—OR¹⁴; R^(12c) is —NO₂, —CN, —S(O)R¹⁵,—SO₂R¹⁵, —SO₂—N(R¹⁶)₂, —C(R¹⁴)═N—OR¹⁴, —N(R¹⁶)C(O)R¹⁵,—N(R¹⁶)C(O)N(R¹⁶)₂, —O—CO₂—R¹⁴—, —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴, —CO₂R¹⁴,—C(O)—C(O)R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—OR¹⁴, —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)—OR¹⁵, —N(R¹⁶)S(O)₂R¹⁵, or—N(R¹⁶)SO₂—N(R¹⁶)₂; each R¹³ is independently hydrogen, or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R¹⁴independently is hydrogen, or an optionally substituted aliphatic, aryl,heteroaryl, or heterocyclyl group; each R¹⁵ independently is anoptionally substituted aliphatic, or aryl group; each R¹⁶ independentlyis an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; or two R¹⁶ on the same nitrogen atom, taken togetherwith the nitrogen atom, form an optionally substituted five to eightmembered heterocylyl ring having, in addition to the nitrogen atom, zeroto two additional ring heteroatoms selected from the group consisting ofN, O, and S; each R²¹ independently is an optionally substituted C₁₋₁₀aliphatic, aryl, heteroaryl, or heterocyclyl group; and m is 1, 2, or 3;provided that if Ring A is A-i, X is —O—, Y is —O— or —CH₂—, R² ishydrogen or chloro, R^(3a) is hydroxyl or —OCOR²¹, R^(3b) is hydrogen,R^(3c) is hydroxyl or —OCOR²¹, R^(3d) is hydrogen, R⁴ and R⁵ are eachhydrogen, and m is 1; then R¹ is bromo, fluoro, —NR⁷R⁸, —R⁹, —SR¹⁰, or—OR¹¹, R⁷ is a substituted aliphatic, or an optionally substituted aryl,heteroaryl, aralkyl, heteroaralkyl, cycloaliphatic, heterocyclyl,(cycloaliphatic)alkyl, or (heterocyclyl)alkyl, and R⁹ is other thanunsubstituted imidazole.
 2. The compound of claim 1, characterized byone or more of the following features: (a) X is —O—; (b) Y is —O— or—CH₂—; (c) R^(3a) is —OH; (d) R^(3b) and R^(3d) are each independentlyhydrogen or C₁₋₄ aliphatic; (e) R^(3c) is hydrogen, fluoro, or —OR⁵; (f)R⁵ and R^(5′) are each hydrogen; (g) each R⁴ is hydrogen; (h) each R² ishydrogen; (i) R^(h) is hydrogen; (j) R^(j) is hydrogen; and (k) R^(k) ishydrogen, halo, or C₁₋₄ aliphatic.
 3. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X is —CH₂—,—NH—, or —O—; Y is —O—, or —CH₂—; Q is ═N— or ═CH—; R¹ is chloro, bromo,fluoro, iodo, —NR⁷R⁸, —S—R¹⁰, or —O—R¹¹; R² is hydrogen, chloro, bromo,fluoro, iodo, —N(R⁶)₂, —CN, —O—(C₁₋₄ aliphatic), —OH, —SR⁶, or anoptionally substituted C₁₋₄ aliphatic group; R^(3a) is selected from thegroup consisting of hydrogen, hydroxy, —NH₂, —C₁₋₄ aliphatic, fluoro,—CN, —C₁₋₄ fluoroaliphatic, —OR²¹, —NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹,—CON(H)R²¹, —OC(O)N(H)R²¹, —OC(O)R²¹, and —OC(O)OR²¹; R^(3b) is selectedfrom the group consisting of hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic; R^(3c) is selected from the group consisting ofhydrogen, hydroxy, —NH₂, —C₁₋₄ aliphatic, fluoro, —CN, —C₁₋₄fluoroaliphatic, —OR²¹, —NH(R²¹), —N(H)CO₂R²¹, —N(H)C(O)R²¹, —CON(H)R²¹,—OC(O)N(H)R²¹, —OC(O)R²¹, and —OC(O)OR²¹; R^(3d) is selected from thegroup consisting of hydrogen, fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic; each R⁴ is independently hydrogen or C₁₋₄ aliphatic; ortwo R⁴, taken together with the carbon atom to which they are attached,form a 3- to 6-membered carbocyclic ring; or one R⁴, taken together withR⁵ and the intervening carbon atoms, forms a 3- to 6-memberedspirocyclic ring; R⁵ is hydrogen, or C₁₋₄ aliphatic; or R⁵, takentogether with one R⁴ and the intervening carbon atoms, forms a 3- to6-membered spirocyclic ring; each R⁶ is independently hydrogen or C₁₋₄aliphatic; R⁷ is an optionally substituted C₁₋₁₀ aliphatic, aryl,heteroaryl, or heterocyclyl group; R⁸ is hydrogen or C₁₋₄ aliphatic; R⁹is —V—Z—R¹, —V—Z—R^(12b), —R^(12c), or an option ally substitutedaliphatic, aryl, heterocyclyl, or heteroaryl group, wherein theheteroaryl group is attached at a carbon atom; is an optionallysubstituted C₂₋₁₀ aliphatic, aryl, heteroaryl, or heterocyclyl; R¹¹ isan optionally substituted C₂₋₁₀ aliphatic, aryl, heteroaryl, orheterocyclyl; V is —S(O)₂—, —S(O)—, —C(O)O—, —C(O)—, —C(NR¹³)═N—,—C(═N(R¹³))—N(R¹³)—, —C(OR¹¹)═N—, —CON(R¹³)—, —N(R¹³)C(O)—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂—, —N(R¹³)SO₂—N(R¹³)—, —N(R¹³)CO₂—,—SO₂N(R¹³)—, —OC(O)—, —OC(O)O—, —OC(O)N(R¹³)—, —N(R¹³)—N(R¹³)—; Z is anoptionally substituted C₁₋₆ alkylene chain, wherein the alkylene chainis optionally interrupted by —C(R¹³)═C(R¹³)—, —C≡C—, —O—, —S—, —N(R¹³)—,—N(R¹³)CO—, —N(R¹³)CO₂—, —C(O)N(R¹³)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —N(R¹³)C(O)N(R¹³)—, —N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—,—S(O)—, —S(O)₂—, —N(R¹³)S(O)₂—, —S(O)₂N(R¹³)—; R^(12a) is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic group;R^(12b) is halo, —NO₂, —CN, —OR¹⁴, —SR¹⁵, —N(R¹⁶)₂, —N(R¹⁶)C(O)R¹⁵,—N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)CO₂R¹⁴, —O—CO₂—R¹⁴, —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴,—N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵, or —N(R¹⁶)SO₂—N(R¹⁶)₂,—C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂,—C(R¹⁴)═N—OR¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴; R^(12c) is —NO₂, —CN, —S(O)R¹⁵,—SO₂R¹⁵, —SO₂—N(R¹⁶)₂, —C(R¹⁴)═N—OR¹⁴, —N(R¹⁶)C(O)R¹⁵,—N(R¹⁶)C(O)N(R¹⁶)₂, —O—CO₂R¹⁴—, —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴, —CO₂R¹⁴,—C(O)—C(O)R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—OR¹⁴, —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵, or —N(R¹⁶)SO₂—N(R¹⁶)₂;each R¹³ is independently hydrogen, or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl group; each R¹⁴independently is hydrogen, or an optionally substituted aliphatic, aryl,heteroaryl, or heterocyclyl group; each R¹⁵ independently is anoptionally substituted aliphatic, or aryl group; each R¹⁶ independentlyis an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; or two R¹⁶ on the same nitrogen atom, taken togetherwith the nitrogen atom, form an optionally substituted five to eightmembered heterocylyl ring having, in addition to the nitrogen atom, zeroto two additional ring heteroatoms selected from the group consisting ofN, O, and S; and each R²¹ independently is an optionally substitutedC₁₋₁₀ aliphatic, aryl, heteroaryl, or heterocyclyl group; provided that:if X is —O—, Y is —O— or —CH₂—, Q is ═N—, R² is hydrogen or chloro,R^(3a) is hydroxyl or —OCOR²¹, R^(3b) is hydrogen, R^(3c) is hydroxyl or—OCOR²¹, R^(3d) is hydrogen, and R⁴ and R⁵ are each hydrogen; then R¹ isbromo, fluoro, —NR⁷R⁸, —R⁹, —SR¹⁰, or —OR¹¹, and R⁷ is a substitutedaliphatic, or an optionally substituted aryl, heteroaryl, aralkyl,heteroaralkyl, cycloaliphatic, heterocyclyl, (cycloaliphatic)alkyl, or(heterocyclyl)alkyl.
 4. The compound of claim 3, characterized by one ormore of the features (a) through (f): (a) R^(3a) is selected from thegroup consisting of hydrogen, hydroxy, methoxy, C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, and fluoro; (b) R^(3b) is hydrogen; (c) R^(3c) ishydrogen or hydroxy; (d) R^(3d) is hydrogen; (e) each R⁴ is hydrogen;and (f) R⁵ is hydrogen.
 5. The compound of claim 4, having the formula(IIA) or (II-B):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim4, having the formula (IIIA) or (III-B):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim4, having the formula (IV-A) or (IV-B):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, characterized by formula (V):

or a pharmaceutically acceptable salt thereof, wherein: Ring B is anoptionally substituted 5- or 6-membered aryl or heteroaryl ring havingzero to three ring nitrogen atoms and optionally one additional ringheteroatom selected from oxygen and sulfur; substitutable ring carbonatoms in Ring B are substituted with 0-2 substituents independentlyselected from the group consisting of C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(a17), —R^(b17), —Z¹⁷—R^(a17), and—Z¹⁷—R^(b17), or two adjacent substituents, taken together with theintervening ring atoms, form an optionally substituted fused 5- or6-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S; Z¹⁷ is an optionallysubstituted C₁₋₆ alkylene chain, wherein the alkylene chain optionallyis interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—,—SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—, —NR¹⁵C(O)N(R¹⁵)—, —N(R¹⁵)CO₂—,—N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, or—OC(O)N(R¹⁵)—, and wherein Z¹⁷ or a portion thereof optionally formspart of a 3-7 membered ring; each R^(a17) independently is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; andeach R^(b17) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)₂, —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴, —N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—N(R¹⁶)SO₂R¹³, —N(R¹⁶) SO₂N(R¹⁶)₂.
 9. The compound of claim 8, whereinRing B is a phenyl ring substituted with 0-2 substituents independentlyselected from the group consisting of halo, —OH, —O(C₁₋₃ alkyl), —CN,—N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂,—C(O)NH(C₁₋₃ alkyl), —C₁₋₃ aliphatic, —C₁₋₃ fluoroaliphatic, —O(C₁₋₃fluoroaliphatic), optionally substituted aryl, and optionallysubstituted heteroaryl.
 10. The compound of claim 1, wherein R¹ is C₁₋₁₀aliphatic, —Z—R^(12a), —Z—R^(12b), -L-Z—R^(12a), -L-Z—R^(12b),-L-R^(12a) or -L-R^(12d); L is —C(R¹³)═C(R¹³)— or —C≡C—; and R^(12d) is—NO₂, —CN, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂, —CO₂R¹⁴, —C(O)R¹⁴, or—C(O)N(R¹⁶).
 11. The compound of claim 1, wherein R¹ is —V—R^(12a),—V—Z—R^(12b), or —Z—V—R^(12a).
 12. The compound of claim 10,characterized by formula (VI):

or a pharmaceutically acceptable salt thereof, wherein: W¹ is —Z—, -L-,—V—, —V—Z—, or —Z—V—; Ring C is an optionally substituted 5- or6-membered aryl, cycloaliphatic, heteroaryl, or heterocyclyl ring havingzero to three ring nitrogen atoms and optionally one additional ringheteroatom selected from oxygen and sulfur; substitutable ring carbonatoms in Ring C are substituted with 0-2 substituents independentlyselected from the group consisting of C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(a12), —R^(b12), —Z¹²—R^(a12), and—Z¹²—R^(b12), or two adjacent substituents on Ring C, taken togetherwith the intervening ring atoms form an optionally substituted fused 5-or 6-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S; Z¹² is an optionallysubstituted C₁₋₆ alkylene chain, wherein the alkylene chain optionallyis interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—,—SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—, —NR¹⁵C(O)N(R¹⁵)—, —N(R¹⁵)CO₂—,—N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, or—OC(O)N(R¹⁵)—, and wherein Z¹² or a portion thereof optionally formspart of a 3-7 membered ring; each R^(a12) independently is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; andeach R^(b12) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, —C(═R¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂. In someembodiments, each R^(b12) independently is —CN, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴—C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —C(O)N(R⁴)₂, —CO₂R⁵, or —OR⁵.
 13. Thecompound of claim 12, wherein: Z is a C₁₋₆ alkylene chain optionallysubstituted with one or two R^(x) or R^(y); each R^(x) independently isselected from the group consisting of -halo, —OH, —O(C₁₋₄ alkyl),—O(C₁₋₄ haloalkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₄alkyl), —CO₂H,—CO₂(C₁₋₄alkyl), —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), or optionally substitutedaryl; each R^(y) independently is a C₁₋₃ aliphatic optionallysubstituted with. R^(x) or an optionally substituted aryl or heteroarylgroup; or two R^(y) on the same carbon atom, taken together with thecarbon atom to which they are attached form a 3- to 6-memberedcycloaliphatic ring; and Ring C is an optionally substituted phenyl ringor an optionally substituted C₃₋₆ cycloaliphatic ring.
 14. The compoundof claim 1, wherein R¹ is —NR⁷R⁸, and the compound is characterized byformula (VII):

or a pharmaceutically acceptable salt thereof, wherein: R⁸ is hydrogenor C₁₋₄ aliphatic; and Ring D is an optionally substituted mono- orbicyclic aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring.
 15. Thecompound of claim 14, wherein: each substitutable saturated ring carbonatom in Ring D is unsubstituted or substituted with ═O, ═S, ═C(R¹⁴)₂,═N—N(R¹⁶)₂, ═N—OR¹⁴, ═N—NHC(O)R¹⁴, ═N—NHCO₂R¹⁵, ═N—NHSO₂R¹⁵; ═N—R¹⁴; or—R^(d); each substitutable unsaturated carbon atom in Ring D isunsubstituted or substituted with —R^(d); each R^(d) independently isselected from the group consisting of C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(a7)C, —R^(b7), —Z⁷—R^(a7), and —Z⁷—R^(b7); Z⁷is an optionally substituted C₁₋₆ alkylene chain, wherein the alkylenechain optionally is interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—, —S—,—S(O)—, —S(O)₂—, —SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—, —NR¹⁵C(O)N(R¹⁵)—,—N(R¹⁵)CO₂—, —N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—, —OC(O)—,—OC(O)O—, or —OC(O)N(R¹⁵)—, and wherein Z⁷ or a portion thereofoptionally forms part of a 3-7 membered ring; each R^(a7) independentlyis an optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring; and each R^(b7) independently is —NO₂, —CN,—C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴, —OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂,—N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴; —NR¹⁶C(O)N(R¹⁶)₂; —NR¹⁶CO₂R¹⁴; —O—CO₂R¹⁴,—OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴, —CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂,—C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂; —C(═NR¹⁶)—N(R¹⁶)₂, —C(═NR¹⁶)—OR¹⁴;—C(R¹⁴)═N—OR¹⁴, —N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵,—N(R¹⁶)SO₂N(R¹⁶)₂.
 16. The compound of claim 15, wherein Ring D is anoptionally substituted phenyl, naphthyl, or indanyl ring.
 17. Thecompound of claim 15, wherein Ring D is selected from the groupconsisting of:

where each R^(8p) independently is selected from the group consisting of═O, fluoro, —OR^(5x), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), provided that R⁸P is other than —OR^(5x) whenlocated at a position adjacent to a ring oxygen atom; s is 0, 1, or 2;and t is 0, 1, or
 2. 18. The compound of claim 1, wherein R¹ is —O—R¹¹,—S—R¹⁰, or —NR⁷R⁸; R⁷, R¹⁰, and R¹¹ are each independently —Z^(a)R¹⁸,—Z^(a)R¹⁹, or —Z^(b)R²⁰; Z^(a) is an optionally substituted C₁₋₆alkylene chain, wherein the alkylene chain is optionally interrupted by—C(R¹³)═C(R¹³)—, —C≡C—, —O—, —S—, —N(R¹³)—, —N(R¹³)CO—, —N(R¹³)CO₂—,—C(O)N(R¹³)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—, —S(O)₂—,—N(R¹³)S(O)₂—, —S(O)₂N(R¹³)—; Z^(b) is an optionally substituted C₂₋₆alkylene chain, wherein the alkylene chain is optionally interrupted by—C(R¹³)═C(R¹³)—, —C≡C—, —O—, —S—, —N(R¹³)—, —N(R¹³)CO—, —N(R¹³)CO₂—,—C(O)N(R¹³)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)N(R¹³)—, —OC(O)N(R¹³)—, —S(O)—, —S(O)₂—,—N(R¹³)S(O)₂—, —S(O)₂N(R¹³)—; R¹⁸ is an optionally substituted aryl,heteroaryl, heterocyclyl, or cycloaliphatic group; R¹⁹ is—C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂—N(R¹⁶)₂,—C(R¹⁴)═N—OR¹⁴, —CO₂R¹⁴, —C(O)—C(O)R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂, or —C(═NR¹⁶)—OR¹⁴; R²⁰ is halo, —NO₂, —CN, —OR¹⁴,SR¹⁵—, —N(R¹⁶)₂, —N(R¹⁶)C(O)R¹⁵, —N(R¹⁶)C(O)N(R¹⁶)₂, —N(R¹⁶)CO₂R¹⁴,—O—CO₂—R¹⁴, —OC(O)N(R¹⁶)₂, —OC(O)R¹⁴, —N(R¹⁶)—N(R¹⁶)₂, —N(R¹⁶)S(O)₂R¹⁵,or —N(R¹⁶)SO₂—N(R¹⁶)₂; and R⁸ is hydrogen.
 19. The compound of claim 18,wherein: Z^(a) is a C₁₋₄ alkylene chain optionally substituted with oneor two groups selected from the group consisting of —F, —OH, C₁₋₃aliphatic and optionally substituted aryl; and Z^(b) is a C₂₋₄ alkylenechain optionally substituted with one or two groups selected from thegroup consisting of —F, —OH, C₁₋₃ aliphatic and optionally substitutedaryl.
 20. The compound of claim 19, characterized by formula (VIII):

or a pharmaceutically acceptable salt thereof; wherein: W² is —O—, —S—,or —N(R⁸)—; Ring E is a mono- or bicyclic aryl, heteroaryl,heterocyclyl, or cycloaliphatic group; each substitutable ring nitrogenatom in Ring E is unsubstituted or is substituted with —C(O)R¹⁴,—C(O)N(R¹⁶)₂, —CO₂R¹⁴, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, or an optionallysubstituted aliphatic; substitutable ring carbon atom in Ring E aresubstituted with 0-4 substituents independently selected from the groupconsisting of C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(a18),—R^(b18), —Z¹⁸—R^(a18), and —Z¹⁸—R^(b18); Z¹⁸ is an optionallysubstituted C₁₋₆ alkylene chain, wherein the alkylene chain optionallyis interrupted by —C(R¹⁴)═C(R¹⁴)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—,—SO₂N(R¹⁵)—, —N(R¹⁵)—, —N(R¹⁵)C(O)—, —NR¹⁵C(O)N(R¹⁵)—, —N(R¹⁵)CO₂—,—N(R¹⁵)SO₂—, —C(O)N(R¹⁵)—, —C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, or—OC(O)N(R¹⁵)—, and wherein Z¹⁸ or a portion thereof optionally formspart of a 3-7 membered ring; each R^(a18) independently is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; andeach R^(b18) independently is —NO₂, —CN, —C(R¹⁴)═C(R¹⁴)₂, —C≡C—R¹⁴,—OR¹⁴, —SR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, —SO₂N(R¹⁶)₂, —N(R¹⁶)₂, —NR¹⁶C(O)R¹⁴,—NR¹⁶C(O)N(R¹⁶)₂, —NR¹⁶CO₂R¹⁴, —O—CO₂R¹⁴, —OC(O)N(R¹⁶)₂, —O—C(O)R¹⁴,—CO₂R¹⁴, —C(O)R¹⁴, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂,—C(═NR¹⁶)—N(R¹⁶)₂. —C(═NR¹⁶)—OR¹⁴, —C(R¹⁴)═N—OR¹⁴,—N(R¹⁶)C(═NR¹⁶)—N(R¹⁶)₂, —N(R¹⁶)SO₂R¹⁵, —N(R¹⁶)SO₂N(R¹⁶)₂.
 21. Thecompound of claim 20, wherein Ring E is a an optionally substituted C₃₋₆cycloaliphatic, phenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyrimidinylring.
 22. The compound of claim 21, wherein Ring E is an optionallysubstituted phenyl, naphthyl, indanyl, furanyl, thienyl, pyrrolyl,pyrrolidinyl, isoxazolyl, pyrazolyl, piperidinyl, piperazinyl,pyrazinyl, morpholinyl, benzothiophenyl, or benzodioxolyl ring.
 23. Apharmaceutical composition, comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 24. A method of decreasing an E1 enzyme activity ina sample, comprising contacting a sample with one or more compoundsaccording to claim
 1. 25. The method of claim 24, wherein the E1 enzymeis selected from the group consisting of NAE, UAE, and SAE.
 26. Themethod of claim 25, wherein the E1 enzyme is NAE.
 27. A method oftreating or ameliorating a disorder in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof one or more compounds according to claim 1, wherein the disorder isselected from the group consisting of cancer, an inflammatory disorder,a neurodegenerative disorder, inflammation associated with infection,and cachexia.
 28. The method of claim 27, wherein the disorder iscancer.
 29. The method of claim 28, wherein the cancer is lung cancer,colorectal cancer, ovarian cancer, or a hematological cancer.
 30. Themethod of claim 27, wherein the disorder is an immune response orvascular cell proliferation disorder.